Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis

Abstract

Malignant testicular germ cell tumors (TGCT) are the most frequent cancers in Caucasian males (20-40 years) with an 70% increasing incidence the last 20 years, probably due to combined action of (epi)genetic and (micro)environmental factors. It is expected that TGCT have carcinoma in situ(CIS) as their common precursor, originating from an embryonic germ cell blocked in its maturation process. The overall cure rate of TGCT is more than 90%, however, men surviving TGCT can present long-term side effects of systemic cancer treatment. In contrast, men diagnosed and treated for CIS only continue to live without these long-term side effects. Therefore, early detection of CIS has great health benefits, which will require an informative screening method. This review described the etiology and early pathogenesis of TGCT, as well as the possibilities of early detection and future potential of screening men at risk for TGCT. For screening, a well-defined risk profile based on both genetic and environmental risk factors is needed. Since 2009, several genome wide association studies (GWAS) have been published, reporting on single-nucleotide polymorphisms (SNPs) with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E, likely to be related to TGCT development. Prenatal, perinatal, and postnatal environmental factors also influence the onset of CIS. A noninvasive early detection method for CIS would be highly beneficial in a clinical setting, for which specific miRNA detection in semen seems to be very promising. Further research is needed to develop a well-defined TGCT risk profile, based on gene-environment interactions, combined with noninvasive detection method for CIS.

Figure 1

Marker expression in normal and impaired testicular development. Marker expression from early embryogenesis till puberty during the normal and impaired testicular development leading to carcinoma in situ (CIS). See text for further explanation. Black sphere: germ cell (not specified for different stages of maturation). Blue sphere: Sertoli cell. Orange sphere: CIS cell. Green bar: normal testicular development (physiological). Red bar: impaired testicular development (pathological).

Figure 2

Genvironmental risk model. The genvironmental risk model shows the different etiological factors which have an influence on the development of testicular germ cell tumors. ¹No association is found for nausea during pregnancy, maternal hypertension, preeclampsia and maternal age. ²No association is found for birth length, breastfeeding and neonatal jaundice. ³Inversely related. ⁴No association is found for smoking and organochlorines exposure. ⁵Working on the paper industry, construction and related occupations, fireman, policemen and military and related occupations. ⁶Pesticides exposures, magnetic and electric field exposure and living in rural areas.

Figure 3

Ultrasonographic abnormalities that may be present in men at risk for testicular germ cell tumors. (a) Testicular microlithiasis in the parenchyma of the testis. (b) Inhomogeneous parenchyma of the testis. (c) Hypo-echoic lesions in the parenchyma of the testis.

Figure 4

Carcinoma in situ (CIS)-cell in semen with OCT3/4 staining. A positive CIS-cell in semen, detected with the immunocytochemical marker OCT3/4.