Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs

Abstract

This concise review summarises tissue and serum markers useful for differential diagnosis of germ cell tumours (GCT), with focus on the most common testicular GCT (TGCT). GCT are characterised by phenotypic heterogeneity due to largely retained embryonic pluripotency and aberrant somatic differentiation. TGCT that occur in young men are divided into two main types, seminoma and nonseminoma, both derived from a pre-invasive germ cell neoplasia in situ (GCNIS), which originates from transformed foetal gonocytes. In severely dysgenetic gonads, a GCNIS-resembling lesion is called gonadoblastoma. GCT occur rarely in young children (infantile GCT) in whom the pathogenesis is different (no GCNIS/gonadoblastoma stage) but the histopathological features are similar to the adult GCT. The rare spermatocytic tumour of older men is derived from post-pubertal spermatogonia that clonally expand due to gain-of function mutations in survival-promoting genes (e.g. FGFR3, HRAS), thus this tumour has a different expression profile than GCNIS-derived TGCT. Clinically most informative immunohistochemical markers for GCT, except teratoma, are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related factors, such as placental-like alkaline phosphatase (PLAP), OCT4 (POU5F1), NANOG, AP-2γ (TFAP2C) and LIN28, which are not expressed in normal adult germ cells. Some of these markers can also be used for immunocytochemistry to detect GCNIS or incipient tumours in semen samples. Gene expression in GCT is regulated in part by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation, except nonseminomas. In addition, a recently discovered mechanism of post-genomic gene expression regulation involves small non-coding RNAs, predominantly micro-RNA (miR). Testicular GCT display micro-RNA profiles similar to embryonic stem cells. Targeted miRNA-based blood tests for miR-371-3 and miR-367 clusters are currently under development and hold a great promise for the future. In some patients miR-based tests may be even more sensitive than the classical serum tumour markers, b-chorio-gonadotrophin (b-hCG), a-fetoprotein (AFP) and lactate dehydrogenase (LDH), which are currently used in the clinic. In summary, research advances have provided clinicians with a panel of molecular markers, which allow specific diagnosis of various subtypes of GCT and are very useful for early detection at the precursor stage and for monitoring of patients during the follow-up.

Mediastinal Germ Cell Tumors in Pediatric Patients: A Report From the Italian Association of Pediatric Hematology and Oncology

“…It may be speculated that the low number of studies in pediatric populations compared to adults may influence this finding. Nevertheless, some cytogenetic and molecular studies have shown profound differences in molecular biology between GCTs arising in infancy and those arising after onset of puberty despite identical histology, suggesting that pediatric GCTs stem from a different stage of germ cell development …”

“…Nevertheless, some cytogenetic and molecular studies have shown profound differences in molecular biology between GCTs arising in infancy and those arising after onset of puberty despite identical histology, suggesting that pediatric GCTs stem from a different stage of germ cell development. [15][16][17][18][19] A risk classification system for pediatric extracranial GCTs has recently been presented. [20] The authors found that age >11 years, ovarian stage IV disease, and extragonadal stages III and IV disease confer a significantly worse prognosis.…”

Influence of Nodal signalling on pluripotency factor expression, tumour cell proliferation and cisplatin-sensitivity in testicular germ cell tumours

“…Tissue fragments with normal morphology and containing complete spermatogenesis without the presence of malignant germ cells were used as 'normal adult testis' controls. All tissue samples were evaluated by an experienced pathologist using a panel of immunohistochemical markers to characterise GCNIS cells and tumour subtypes, including placental-like alkaline phosphatase (PLAP), podoplanin (PDPN/D2-40), OCT4 (POU5F1), and (for non-SEMs only) also alpha-fetoprotein (AFP) and beta-choriogonadotropin (hCG) [27]. Frozen tissue specimens used for gene expression analysis were sectioned from each end of the tissue fragment and evaluated using immunohistochemistry to confirm the histological tumour subtype prior to RNA extraction.…”

Overexpression of TET dioxygenases in seminomas associates with low levels of DNA methylation and hydroxymethylation

“…This agrees with previous demonstration of pluripotent marker expression in GCTs (excluding teratoma) and in PGCs/ gonocytes. These markers include highly expressed embryonic factors involved in the pluripotency maintenance, including OCT4 and NANOG, 67 and transcription factor SALL4. 44 The highest levels of pluripotent marker expression in seminomas further underlines the germ cell origin of the seminomas and stresses out the reprograming occurring during the transition to non-seminomas.…”