Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
Department of Pathology, Nowon Eulji Medical Center, Eulji University, Seoul, Republic of Korea.
Gut. 2022 May;71(5):961-973. doi: 10.1136/gutjnl-2020-322595. Epub 2021 Apr 13.
Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.
An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).
ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).
ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
最近的研究发现，类 Aristaless 同源盒基因（ARX）/胰腺和十二指肠同源盒 1（PDX1）、α-地中海贫血/智力低下 X 连锁（ATRX）/死亡域相关蛋白（DAXX）和端粒的替代延长（ALT）是无功能胰腺神经内分泌肿瘤（NF-PanNETs）有前途的预后生物标志物。然而，它们尚未得到全面评估，尤其是在小的 NF-PanNETs（≤2.0 cm）中。此外，它们在其他部位的神经内分泌肿瘤（NETs）中的状态尚不清楚。
通过免疫标记 ARX/PDX1 和 ATRX/DAXX 以及端粒特异性荧光原位杂交法评估 ALT，对 1322 例 NETs 的国际队列进行了评估。该队列包括 561 例原发性 NF-PanNETs、107 例 NF-PanNET 转移和 654 例原发性、非胰腺非功能性 NETs 和 NET 转移。结果与包括无复发生存率（RFS）在内的许多临床病理特征相关。
ATRX/DAXX 缺失和 ALT 与多种不良预后发现和远处转移/复发相关（p<0.001）。ATRXX/DAXX 阴性和 ALT 阳性 NF-PanNETs 患者的 5 年 RFS 率分别为 40%和 42%，而野生型 NF-PanNETs 的 5 年 RFS 率分别为 85%和 86%（p<0.001 和 p<0.001）。≤2.0 cm NF-PanNETs 患者的 5 年 RFS 率也较短，ATRX/DAXX 缺失（65%比 92%，p=0.003）和 ALT（60%比 93%，p<0.001）。多变量分析显示，ATRX/DAXX 和 ALT 状态是 RFS 的独立预后因素。相反，根据 ARX/PDX1 表达对 NF-PanNETs 进行分类与 RFS 无独立相关性。除了 4%的肺类癌外，ATRXX/DAXX 缺失和 ALT 仅在原发性（25%和 29%）和 NF-PanNET 转移（62%和 71%）中发现。
ATRXX/DAXX 和 ALT 应考虑用于包括≤2.0 cm 肿瘤在内的 NF-PanNETs 的预后评估，并且在未知原发性 NETs 的胰腺转移中高度特异性。
