Circulating Tumor Cells in Patients with Testicular Germ Cell Tumors

Abstract

Purpose: Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell-specific markers, and results were correlated with disease stage, histology, and serum tumor markers.Experimental Design: CTCs were enriched from peripheral blood (n ¼ 143 patients) and testicular vein blood (TVB, n ¼ 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell-specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system.Results: In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P ¼ 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of a-fetoprotein (AFP; P ¼ 0.025), b-human chorionic gonadotropin (bHCG; P ¼ 0.002), and lactate dehydrogenase (LDH; P ¼ 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood.Conclusions: The inclusion of germ cell tumor-specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery.

Clinical and biological significance of circulating tumor cells in cancer

“…In nonmetastatic colorectal cancer (CRC), pre‐operative CTC detection was reported to be an independent prognostic marker (Bork et al., 2015). In testicular germ cell tumors, the presence of CTCs in the PB was shown to be correlated with clinical stage in 41% of CTC‐positive patients with metastasized tumors and in 100% of patients with relapsed and chemotherapy‐refractory disease (Nastaly et al., 2014). Similar results were reported in esophageal cancer (Reeh et al., 2015) and squamous cell carcinoma of the oral cavity (Grover et al., 2014).…”

SALL4, the missing link between stem cells, development and cancer

“…In yolk sac tumors and primary extragonadal germ cell tumors, one study reported that the circulating tumor cells are detectable by anti-SALL4 antibody in peripheral blood samples, making this protein a more sensitive marker than α-fetoprotein and glypican-3 107 . In addition, SALL4 is expressed in a majority of malignant rhabdoid tumors (MRTs) 20108109110111 but rarely expressed in epithelioid sarcomas.…”

Mediastinal germ cell tumour causing superior vena cava tumour thrombosis

“…Therefore, research is starting to identify the role of circulating tumour cells (CTCs), which are detected in approximately 18% of GCTs. Non-seminomatous tumours associated with CTCs have more aggressive, clinically advanced cancer with increased metastatic potential and disease progression, and are treatment refractory 13. While numerous clinical studies exist on the role and detection of CTCs in metastatic breast, colon and prostate cancer,14–16 little is known in the context of GCTs.…”