Study Type - Therapy (case series) Level of Evidence 4 OBJECTIVE: To describe the histopathological types of late relapses of germ cell tumours and to search for molecular markers associated with chemotherapy resistance. PATIENTS AND METHODS: Samples from 14 patients with late relapse from a non-seminoma were analysed. Archival tumour tissue was gathered at intial diagnosis (n= 9) and at relapse (n= 9), mostly after previous treatment with chemotherapy. In addition to routine histopathology, tumours were analysed for microsatellite instability and screened for mutations in the KRAS and BRAF genes. RESULTS: Relapse occurred after 76.5 months (median, range: 24-209 months). The histology in relapse was pure yolk sac tumour in four of the nine patients analysed. Three had a non-germ cell malignancy, one was a mixed non-seminoma and one was a pure mature teratoma. One sample with non-germ cell malignancy originated from a yolk sac tumour without any evidence of teratoma. In four of 12 evaluable patients, high-level microsatellite instability was observed. All patients were KRAS wild-type but four showed a BRAF mutation at V600E. CONCLUSION: Many late relapses of germ cell tumours show pure yolk sac histology. Non-germ cell malignancies do not necessarily develop from teratoma but can also arise from yolk sac histology. The biology underlying chemotherapy resistance in late relapse could be related to a high incidence of microsatellite instability and BRAF mutation V600E, which were found in half of the patients.
