Histopathological and molecular features of late relapses in non-seminomas.
OBJECTIVE
• To describe the histopathological types of late relapses of germ cell tumours and to search for molecular markers associated with chemotherapy resistance.


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.


CONCLUSIONS
• 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.
Mayer
Frank
F
Department of Oncology, Haematology, Immunology, Rheumathology and Pulmology, University of Tübingen Medical Centre, Tübingen, Germany. frank.mayer@med.uni-tuebingen.de
Wermann
Hendrik
H
Albers
Peter
P
Stoop
Hans
H
Gillis
Ad J M
AJ
Hartmann
Jörg T
JT
Bokemeyer
C Carsten
CC
Oosterhuis
J Wolter
JW
Looijenga
Leendert H J
LH
Honecker
Friedemann
F
D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000556:secondary; D009919:Orchiectomy / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins