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.
Department of Oncology, Haematology, Immunology, Rheumathology and Pulmology, University of Tübingen Medical Centre, Tübingen, Germany. frank.mayer@med.uni-tuebingen.de
Frank
F
Mayer
Hendrik
H
Wermann
Peter
P
Albers
Hans
H
Stoop
Ad J M
AJ
Gillis
Jörg T
JT
Hartmann
C Carsten
CC
Bokemeyer
J Wolter
JW
Oosterhuis
Leendert H J
LH
Looijenga
Friedemann
F
Honecker
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