Molecular subtyping in pancreatic neuroendocrine neoplasms: New insights into clinical, pathological unmet needs and challenges

Abstract

Pancreatic neuroendocrine neoplasms (PanNENs) contain two primary subtypes with distinct molecular features and associated clinical outcomes: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). PanNENs are a group of clinically heterogeneous tumors, whose diagnosis is based on tumor morphologic features and proliferation indices. However, these standards incompletely meet clinical needs by failing to adequately assess the likelihood of tumor recurrence and the potential for therapeutic response. We therefore focused on discussing molecular advances that facilitate the understanding of heterogeneity and exploration of reliable recurrence/treatment predictors. Taking advantage of high-throughput technologies, emerging methods of molecular subtyping in PanNETs include classifications based on co-existing multi-gene mutations, a large-scale loss of heterozygosity or copy number variation, and islet cell type-specific signatures. PanNEC molecular updates were discussed as well. This review aims to help the field classify PanNEN molecular subtypes, gain insights to aid in the solving of clinical, pathological unmet needs, and detect challenges and concerns of genetically-driven trials.

Keywords: High throughput nucleotide sequencing; Molecular subtyping; Multiomics-integrated analysis; Neuroendocrine carcinoma; Pancreatic neuroendocrine tumor; α cell signature.