许多胰腺神经内分泌肿瘤(PanNETs)根据DAXX/ATRX诱导的ALT表型以及α和β细胞样表观基因组谱分为两种主要的预后亚型。然而,这些PanNETs的两侧仍然是其他不适合任何亚型的PanNETs。此外,尽管先进的基因分型,PanNETs通常在其组织学和激素表型方面没有很好地表征。我们旨在通过扩展目前使用的转录因子标签来鉴定新的PanNETs亚组,并研究它们与组织学的相关性,激素分子和预后结果。在1996年至2023年之间切除的185个PanNETs(无功能165,有功能20个)分为五个亚组(A1,A2,B,C,D)通过基于ARX的聚类分析,PDX1、ISL1和CDX2表达与骨小梁的关系实体组织学,胰岛素的表达,胰高血糖素,PP,生长抑素,血清素,胃泌素,降钙素,ACTH,DAXX/ATRX,MEN1和ALT状态通过FISH,无病生存率(DFS)。A1(46%,ARX+/ISL1+/PDX1-/CDX2-)和A2(15%,ARX+/ISL1+/PDX1+/CDX2-)显示小梁组织学和胰高血糖素/PP表达,A2也显示胃泌素表达。B(18%,PDX1+/ISL1+/ARX-/CDX2-)显示组织学实性,胰岛素和生长抑素表达(p<0.001)。它包括所有胰岛素瘤,并有最好的结果(p<0.01)。C(15%,ARX-/PDX1-/ISL1-/CDX2-)显示出坚实的组织学和5-羟色胺的频繁表达,降钙素和ACTH。D(5%,PDX1+/CDX2+/ISL1-/ARX-)显示为实性组织学,表达ACTH/5-羟色胺,是独立的不良预后因子(p<0.01)。ARX的差异表达,PDX1,ISL1和CDX2将PanNETs分为五个不同组织学的亚组,激素表达和结果。亚组A1和A2类似于α细胞样类型,B亚组为β细胞样类型。几乎没有转录因子特征的C亚组在细胞系中不清楚,而D亚组的PDX+/CDX2+特征提示胰腺/肠细胞谱系。将PanNETs分配给亚组可能有助于建立诊断,预测结果,并指导治疗。
Many pancreatic neuroendocrine tumors (PanNETs) fall into 2 major prognostic subtypes based on DAXX/ATRX-induced alternative lengthening of telomerase phenotype and alpha- and beta-cell-like epigenomic profiles. However, these PanNETs are still flanked by other PanNETs that do not fit into either subtype. Furthermore, despite advanced genotyping, PanNETs are generally not well-characterized in terms of their histologic and hormonal phenotypes. We aimed to identify new
subgroups of PanNETs by extending the currently used transcription factor signatures and investigating their correlation with histologic, hormonal, molecular, and prognostic findings. One hundred eighty-five PanNETs (nonfunctioning 165 and functioning 20), resected between 1996 and 2023, were classified into 5
subgroups (A1, A2, B, C, and D) by cluster analysis based on ARX, PDX1, islet-1 (ISL1), and CDX2 expressions and correlated with trabecular vs solid histology, expression of insulin, glucagon, polypeptide (PP), somatostatin, serotonin, gastrin, calcitonin, adrenocorticotropic hormone (ACTH), DAXX/ATRX, MEN1, and alternative lengthening of telomerase status by fluorescence in situ hybridization, and disease-free survival. A1 (46%, ARX+/ISL1+/PDX1-/CDX2-) and A2 (15%, ARX+/ISL1+/PDX1+/CDX2-) showed trabecular histology and glucagon/PP expression, with A2 also showing gastrin expression. B (18%, PDX1+/ISL1+/ARX-/CDX2-) showed solid histology, insulin, and somatostatin expression (P < .001). It included all insulinomas and had the best outcome (P < .01). C (15%, ARX-/PDX1-/ISL1-/CDX2-) showed solid histology and frequent expression of serotonin, calcitonin, and ACTH. D (5%, PDX1+/CDX2+/ISL1-/ARX-) showed solid histology, expressed ACTH/serotonin, and was an independent poor prognosticator (P < .01). Differential expressions of ARX, PDX1, ISL1, and CDX2 stratified PanNETs into 5
subgroups with different histologies, hormone expressions, and outcomes.
Subgroups A1 and A2 resembled the alpha-cell-like type, and subgroup B, the beta-cell-like type. Subgroup C with almost no transcription factor signature was unclear in cell lineage, whereas the PDX+/CDX2+ signature of subgroup D suggested a pancreatic/intestinal cell lineage. Assigning PanNETs to the
subgroups may help establish the diagnosis, predict the outcome, and guide the treatment.