In the gastro-entero-pancreatic (GEP) tract, neuroendocrine neoplasms (NENs) include well differentiated neuroendocrine tumors (NETs) and high-grade NE carcinomas (NECs), which are thought to make up separate and mutually exclusive tumor entities. Little is known, however, as to whether there may be any pathogenetic link between them. Clustering analysis of a 10-gene panel generated from a previously reported next-generation sequencing analysis on 48 GEP-NENs with clinical annotations was used in the study. Unsupervised cluster analysis showed three histology-independent clusters, namely, C1, C2, and C3, which accounted for 44% of patients but the entire array of mutations. All but two NECs fell into the clusters, yet with different prevalence rates (p < 0.0001). A model was devised according to which NETs were likely to evolve into NECs upon progression of C3 into C1 and C2, despite different morphology. The median Ki-67 labeling index was 5% in C3 showing better prognosis and 50% in C1 and C2 experiencing worse prognosis, with an impressive intra-tumor heterogeneity of diversely proliferating tumor areas. This study suggests that a subset of large cell NECs in the gastroenteropancreatic tract may evolve from pre-existing well-differentiated NETs.

在胃肠胰 (GEP) 道中，神经内分泌肿瘤 (NEN) 包括分化良好的神经内分泌肿瘤 (NET) 和高级别 NE 癌 (NEC)，它们被认为是独立且相互排斥的肿瘤实体。然而，关于它们之间是否可能存在任何致病联系，我们知之甚少。该研究使用了从先前报道的对 48 个 GEP-NEN 进行的下一代测序分析生成的 10 基因组的聚类分析，并带有临床注释。无监督聚类分析显示三个独立于组织学的聚类，即 C1、C2 和 C3，占患者的 44%，但占整个突变阵列。除两个 NEC 外，所有 NEC 均属于集群，但患病率不同（p < 0.0001)。设计了一个模型，根据该模型，尽管形态不同，但在 C3 进展为 C1 和 C2 时 NET 可能演变为 NEC。中位 Ki-67 标记指数在 C3 中为 5%，表明预后较好，在 C1 和 C2 中为 50%，预后较差，不同增殖的肿瘤区域具有令人印象深刻的肿瘤内异质性。这项研究表明，胃肠胰管中的一部分大细胞 NEC 可能从预先存在的分化良好的 NET 进化而来。