Testicular germ cell tumors: the changing role of the pathologist

Testicular germ cell tumors (TGCTs) are a heterogeneous group of neoplasms derived from neoplastic transformation of germ cells in the testis, but with different epidemiological, biological and clinical settings, from early life to adulthood. In the latest years, several studies led to a deeper understanding of the genetic and biological events characterizing the development and progression of these neoplasms, at the basis of their divergent clinical behaviour. As a result, major and minor modifications regarding their classification criteria and staging parameters have been introduced. The recently published article by Lobo et al. highlighted the new challenges that TGCTs pose to pathologists (1). The latest WHO classification of TGCTs assigns a primary taxonomic role to germ cell neoplasia in situ (GCNIS), which is considered the main precursor lesion of TGCTs (2). In the past, different names have been used to refer to this entity, including “carcinoma in situ” (CIS), “intratubular germ cell neoplasia, unclassified” (IGCNU) and “testicular intraepithelial neoplasia” (TIN) (3). GCNIS is histologically defined as the neoplastic germ cells exclusively localized within the seminiferous tubules. These cells are characterized by enlarged hyperchromatic nuclei, clumped chromatin and often prominent nucleoli and closely resemble seminoma cells (4). In classic GCNIS, the neoplastic germ cells are distributed along the basal membrane of normal-sized seminiferous tubules, with still recognizable Sertoli cells but in absence of spermatogenesis. Involvement of seminiferous tubules is usually patchy and pagetoid spread of GCNIS into tubules with retained spermatogenesis and into the rete testis may also be seen (5,6). Apart from the so far described classical form, two other specific types of GCNIS are recognized, namely intratubular seminomas and intratubular non-seminomas. These variants are almost constantly associated with the presence of classic GCNIS as well as an invasive germ cell tumor and are histologically characterized by a more evident architectural alteration of the tubules, which appear enlarged and completely filled with neoplastic cells with loss of the Sertoli component. Neoplastic cells in intratubular seminoma are morphologically indistinguishable from those of GCNIS (seminoma-like cells) while a higher degree of cellular pleomorphism with greater atypia is seen in intratubular non-seminomas, whose neoplastic cells show morphological and immunohistochemical similarity to embryonal carcinoma cells and are frequently associated with intratubular