Gisder Doreen Maria, Overheu Oliver, Keller Julia, Nöpel-Dünnebacke Stefanie, Uhl Waldemar, Reinacher-Schick Anke, Tannapfel Andrea, Tischoff Iris
Institute of Pathology, Ruhr Universität Bochum, Bochum, Germany.
Department of Haematology and Oncology with Palliative Care, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
Pathobiology. 2023;90(2):71-80. doi: 10.1159/000524920. Epub 2022 Jun 10.
Studies on pancreatic neuroendocrine tumors (PanNETs) regarding loss of ATRX, DAXX, or frequency of microsatellite instability (MSI) show inconclusive results. So far, data on corresponding metastaseshave not been published.
We performed immunohistochemistry (IHC) of ATRX, DAXX, MSH2, MSH6, MLH1, and PMS2 on 74 PanNETs and 19 metastases. ATRX- and DAXX-negative PanNETs were further sequenced for mutations. We used polymerase chain reaction for MSI on cases with IHC loss of MSH2, MSH6, MLH1, and PMS2.
Immunohistochemical loss of DAXX and ATRX was observed in 8/74 (11%) and 6/74 (8%) PanNETs. Loss of DAXX immunoreactivity was statistically associated with higher tumor grade and showed a tendency toward a decreased overall survival. Sequencing of DAXX- (7/11 [64%]) and ATRX-negative (5/11 [45%]) PanNETs revealed a mutation in 6/7 (86%) and 2/5 (40%). The specificity of immunohistochemical loss of DAXX and ATRX for mutation was 80% and 67%, respectively. The expression status of 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.
DISCUSSION/CONCLUSION: Our study supports the hypothesis that a loss of DAXX immunoreactivity can identify a more aggressive subtype of PanNET with high confidence, while ATRX loss is a weaker indicator. Our results also strengthen the role of DAXX immunolabeling as a prognostic marker. We could show that ATRX might be less suitable as a surrogate for sequencing. Our results indicate that IHC of DAXX and ATRX may identify PanNET subtypes as targets for more aggressive therapy.
关于胰腺神经内分泌肿瘤（PanNETs）中ATRX、DAXX缺失或微卫星不稳定性（MSI）频率的研究结果尚无定论。到目前为止，关于相应转移灶的数据尚未发表。
我们对74例PanNETs和19例转移灶进行了ATRX、DAXX、MSH2、MSH6、MLH1和PMS2的免疫组织化学（IHC）检测。对ATRX和DAXX阴性的PanNETs进一步进行突变测序。我们对MSH2、MSH6、MLH1和PMS2免疫组化缺失的病例采用聚合酶链反应检测MSI。
在74例PanNETs中，分别有8/74（11%）和6/74（8%）观察到DAXX和ATRX的免疫组化缺失。DAXX免疫反应性缺失与更高的肿瘤分级在统计学上相关，并且显示出总生存期降低的趋势。对DAXX阴性（7/11 [64%]）和ATRX阴性（5/11 [45%]）的PanNETs进行测序，发现6/7（86%）和2/5（40%）存在突变。DAXX和ATRX免疫组化缺失对突变的特异性分别为80%和67%。与原发肿瘤相比，DAXX的表达状态在2/12（17%）的淋巴结转移灶中有所不同。我们进一步鉴定出3/74（4%）的肿瘤为MSI，其预后较差。
讨论/结论：我们的研究支持这样的假设，即DAXX免疫反应性缺失能够高度可靠地识别出更具侵袭性的PanNETs亚型，而ATRX缺失则是一个较弱的指标。我们的结果也强化了DAXX免疫标记作为预后标志物的作用。我们可以表明，ATRX可能不太适合作为测序的替代指标。我们的结果表明，DAXX和ATRX的免疫组化可能识别出PanNETs亚型，作为更积极治疗的靶点。
