Long-term survival and molecular heterogeneity of sporadic multifocal non-functional pancreatic neuroendocrine tumors.

Multifocal sporadic non-functional pancreatic neuroendocrine tumors (NF-PanNETs) are rare, and their molecular underpinnings remain poorly understood. This study performed whole-exome sequencing on 35 synchronous primary tumors from 9 patients to characterize somatic alterations, copy-number variations, and clonal evolution. We found that multifocality was an independent risk factor for early recurrence. Significant intertumoral genomic heterogeneity was observed, with high discordance in both SNVs and CNVs between lesions. Enrichment of ATRX/MEN1 mutations in multifocal cases suggested a potential link to multifocality. Clonal evolution analysis revealed two distinct patterns: independent tumorigenesis (often associated with germline mutations) and intra-pancreatic metastatic spread. MEN1 mutations were further associated with increased M2 macrophage infiltration. These findings highlight the substantial molecular heterogeneity in multifocal NF-PanNETs and underscore the need for comprehensive lesion profiling and tailored therapeutic strategies based on genomic evolution patterns.