Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.

中文翻译：

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在疾病演变过程中改变 NET 的生物学行为：进展的进展。

随着近年来神经内分泌肿瘤 (NEN) 管理和结果的改善，我们看到了一个子集，尤其是胰腺 NEN，它们在疾病过程中变得更具侵袭性。这反映在作为增殖标志物的 Ki-67 标记指数的增加上，这可能导致分级增加，但通常似乎与组织学证实的去分化无关。直到 2020 年 5 月，对 PubMed、Cochrane 图书馆和 Embase 的文献进行了系统回顾，以确定以这种方式表现的案例。我们筛选了 244 篇文章：只有 7 项研究将病例纳入他们的队列或研究队列的一个子集，通过额外的活检证实在随访期间 Ki-67 有所增加。除了这些研究，我们还试图确定与晚期 NEN 相关的可能的病理生理机制，尽管目前似乎没有研究表明在疾病过程中转变为更具侵袭性的生物学表型所涉及的机制。疾病进程的这种进展可能需要改变管理。总结整体证据，我们建议未来的研究应该集中在疾病进展过程中分子途径的变化，并通过连续活检来阐明使肿瘤比其初始表型或基因型更具侵袭性的机制。尽管目前似乎没有研究表明在疾病过程中转变为更具侵袭性的生物学表型所涉及的机制。疾病进程的这种进展可能需要改变管理。总结整体证据，我们建议未来的研究应该集中在疾病进展过程中分子途径的变化，并通过连续活检来阐明使肿瘤比其初始表型或基因型更具侵袭性的机制。尽管目前似乎没有研究表明在疾病过程中转变为更具侵袭性的生物学表型所涉及的机制。疾病进程的这种进展可能需要改变管理。总结整体证据，我们建议未来的研究应该集中在疾病进展过程中分子途径的变化，并通过连续活检来阐明使肿瘤比其初始表型或基因型更具侵袭性的机制。