Spatiotemporal heterogeneity and clinical challenge of pancreatic neuroendocrine tumors

During the course of pancreatic neuroendocrine tumors (NETs), they generally become more heterogeneous with individual cells exhibiting distinct molecular fingerprints. This heterogeneity manifests itself through an unequal distribution of genetically-variant, tumor cell subpopulations within disease locations (i.e., spatial heterogeneity) or changes in the genomic landscape over time (i.e., temporal heterogeneity); these characteristics complicate clinical diagnosis and treatment. Effective, feasible tumor heterogeneity detection and eradication methods are essential to overcome the clinical challenges of pancreatic NETs. This review explores the molecular fingerprints of pancreatic NETs and the spectrum of tumoral heterogeneity. We then describe the challenges of assessing heterogeneity by liquid biopsies and imaging modalities and the therapeutic challenges for pancreatic NETs. In general, navigating these challenges, refining approaches for translational research, and ultimately improving patient care are available once we have a better understanding of intratumoral spatiotemporal heterogeneity.