<b><i>DAXX</i></b>, <b><i>ATRX</i></b>, and MSI in PanNET and Their Metastases: Correlation with Histopathological Data and Prognosis

Abstract

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