Intratubular Germ Cell Neoplasia of the Testis

Abstract

Germ cell tumors of the testis may be divided into 3 broad categories according to age at presentation. The tumors in the pediatric age group include teratoma and yolk sac tumor. These tumors are generally not associated with convincing intratubular neoplasia. The second group consists of tumors presenting in third and fourth decade of life and include seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma as well as mixed germ cell tumors. The precursor cell for these tumors is an abnormal gonocyte that fails to differentiate completely into spermatogonia. These abnormal cells stay dormant in the gonad during intrauterine life as well as infancy and childhood, but undergo proliferation during puberty and can be identified as intratubular germ cell neoplasia unclassified (IGCNU). These tumor cells continue to manifest protein expression pattern that resembles primitive germ cells (PLAP, c-KIT, OCT3/4). After a variable interval following puberty, IGCNU cells may acquire ability to penetrate the seminiferous tubules and present as an overt germ cell tumor. Acquisition of isochrome 12 and other genetic abnormalities are usually associated with this transition. The level of DNA methylation generally determines the phenotype of the germ cell tumor. The third type of germ cell tumors is spermatocytic seminoma, which is a rare tumor encountered later in life usually in fifth and sixth decade. The cell of origin of this tumor is probably postpubertal mature spermatogonia which acquire abnormal proliferative capability probably due to gain of chromosome 9 resulting in activation and amplification of genes such as DMRT1. The tumor cells manifest many of the proteins normally expressed by mature sperms such as VASA, SSX2, and occasionally OCT2. Although spermatocytic seminoma may also have an intratubular growth phase, it completely lacks features of IGCNU.

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

“…This progenitor shares many characteristics of a primordial germ cell (PGC)/ gonocyte, such as mRNA/miRNA/protein expression (including the coexpression of POU5F1 [also known as OCT3/4] and SOX17) (Looijenga et al 2003;de Jong et al 2008), as well as global CpG methylation erasure, features also found in invasive SE (Port et al 2005;Netto et al 2008;Wermann et al 2010;Al-Hussain et al 2015). However, while PGCs express multiple biomarkers of pluripotency shared with blastocyst inner cell mass stem cells, they are normally unipotent to produce gametogenic stem cells, and the spawning of differentiated somatic elements in this lineage is pathologic.…”

Testicular Germ Cell Tumors

“…The different histologic types of type II GCT are intimately related. The precursor lesion of GCT, GCNIS, shares many phenotypical and morphologic features with seminoma, suggesting a precursor relationship [57][58][59]. However, molecular abnormalities more characteristic of other forms of invasive GCT, such as embryonal carcinoma (EC) or YST, can also be seen in GCNIS, suggesting that the in situ lesion may also play a role of precursor to other forms of GCT as well [57].…”

“…Intratubular teratoma [86] and YST [87] have also been reported. Intratubular ST shows the three characteristic types of cells of the invasive counterpart (see below) and is always associated with an invasive component [58]. Metastatic carcinomas to the testis may show involvement of seminiferous tubules resembling GCNIS [88].…”

“…Microscopically, GCNIS is characterized by the presence of large cells with clear cytoplasm, conspicuous cell membranes, enlarged and hyperchromatic nuclei, and prominent nucleoli ( Fig. 7.2) [58]. These cells stand out in low power and are usually found in the basal layer of seminiferous tubules with atrophic features.…”

“…Gonadal stromal cells express transcription factor SRY, which results in early development of Sertoli cells through the activation of SOX9 [58]. Sertoli cells create a microenvironment that allows differentiation of gonocytes into spermatogonia.…”