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Doreen Maria Gisder, Oliver Overheu, Julia Keller, Stefanie Nöpel-Dünnebacke, Waldemar Uhl, Anke Claudia Reinacher-Schick, Andrea Tannapfel, Iris Tischoff

• \(\bf Introduction:\) Studies on pancreatic neuroendocrine tumors (PanNETs) regarding loss of \(\it ATRX\), \(\it DAXX\), or frequency of microsatellite instability (MSI) show inconclusive results. So far, data on corresponding metastaseshave not been published. \(\bf Methods:\) We performed immunohistochemistry (IHC) of \(\it ATRX\), \(\it DAXX\), (\it MSH2\), (\it MSH6\), (\it MLH1\), and (\it PMS2\) on 74 PanNETs and 19 metastases. \(\it ATRX\)- and \(\it DAXX\)-negative PanNETs were further sequenced for mutations. We used polymerase chain reaction for MSI on cases with IHC loss of (\it MSH2\), (\it MSH6\), (\it MLH1\), and (\it PMS2\). \(\bf Results:\) Immunohistochemical loss of \(\it DAXX\) and \(\it ATRX\) was observed in 8/74 (11%) and 6/74 (8%) PanNETs. Loss of \(\it DAXX\) immunoreactivity was statistically associated with higher tumor grade and showed a tendency toward a decreased overall survival. Sequencing of \(\it DAXX\)- (7/11 [64%]) and \(\it ATRX\)-negative (5/11 [45%]) PanNETs revealed a mutation in 6/7 (86%) and 2/5 (40%). The specificity of immunohistochemical loss of \(\it DAXX\) and \(\it ATRX\) for mutation was 80% and 67%, respectively. The expression status of \(\it DAXX\) compared to primary tumor differs in 2/12 (17%) lymph node metastases. We further identified 3/74 (4%) tumors as MSI, associated with a poor prognosis. \(\bf Discussion/Conclusion:\) Our study supports the hypothesis that a loss of \(\it DAXX\) immunoreactivity can identify a more aggressive subtype of PanNET with high confidence, while \(\it ATRX\) loss is a weaker indicator. Our results also strengthen the role of \(\it DAXX\) immunolabeling as a prognostic marker. We could show that \(\it ATRX\) might be less suitable as a surrogate for sequencing. Our results indicate that IHC of \(\it DAXX\) and \(\it ATRX\) may identify PanNET subtypes as targets for more aggressive therapy.