The Stem Cell Origin and Pathogenetic Routes of Testicular Germ Cell Tumors

Different pathogenetic theories have been put forward about the origin of germ cell tumors (GCTs): some of the evidence is strongly supported by widespread consensus among experts, while the oncogenic pathways are still questioned [1]. Most GCTs of the testis evolve from a common neoplastic precursor: germ cell neoplasia in situ (also called carcinoma in situ [CIS], intratubular germ cell neoplasia, and testicular intratubular neoplasia; see Chap. 6). Many experts believe CIS to be at the origin of two different pathways: one leading to seminoma as the end-stage tumor and the other leading to embryonal carcinoma (EC) [2], which is considered a step in the differentiation into yolk sac tumor (YST), teratoma, or choriocarcinoma. The current hypothesis is that CIS cells are the neoplastic counterparts of primordial germ cells or gonocytes [3], with malignant transformation being induced by blocked maturation of the gonocyte in utero, which causes testicular maldevelopment (“dysgenesis”) [4, 5]. An alternative hypothesis is that seminomas may evolve into other types of GCT. In 1946 Friedman and Moore [6] reported the existence of seminomas that evolved into ECs; recently, the immunophenotypic switch of tumor cells from seminoma to nonseminomatous features (“reprogramming”) with activation of pluripotency was demonstrated [4]. Autopsy findings are consistent with this theory: the presence of nonseminomatous metastases in men with a history of seminoma [7] and the occurrence of retroperitoneal metastases with different histology from the testicular primary are additional evidence supporting it.