Changing biological behaviour of NETs during the evolution of the disease: Progress on progression

Abstract

Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancre atic NENs, which become more aggressive during the course of the disease. This is reflec ted 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 correl ated 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 p roven 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 c ourse of the disease. Such progression of the disease course may demand a change in t he 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.