| Summary: | Background: We aimed to study the effect of socioeconomic differences and molecular characteristics on survival in patients with young-onset pancreatic neuroendocrine tumors (YOPNET) and typical-onset PNET (TOPNET). Methods: We identified the patients with YOPNET (<50 years) and TOPNET (≥50 years) who underwent definitive surgery diagnosed between 2004 and 2016 using the National Cancer Database. We evaluated overall survival (OS) using the Kaplan–Meier and Cox regression methods before and after propensity score matching. A publicly available genomic dataset was used to compare mutation frequencies among the two groups. Results: A total of 6259 patients with PNET were included, of which 27% were YOPNET. Patients with YOPNET were more likely to be Black, Hispanic, female, and have private insurance versus patients with TOPNET (all <i>p</i> < 0.001). Patients with YOPNET had a lower comorbidity score, but higher stage and tumor size (all <i>p</i> < 0.001). YOPNET was associated with a greater improved OS than TOPNET before and after propensity score matching (<i>p</i> < 0.001). On multivariable analysis, this survival difference persisted for YOPNET as an independent prognostic factor (unmatched <i>p</i> = 0.008; matched <i>p</i> = 0.01). For genomic analysis, patients with YOPNET had a lower rate of multiple endocrine neoplasia type-1 (MEN-1) mutation than patients with TOPNET (26% vs. 56%, <i>p</i> < 0.001). Conclusions: YOPNET represents a disease with distinct clinical features. Patients with YOPNET who underwent definitive surgery had better OS than patients with TOPNET despite having higher stage and tumor size. YOPNET also had lower rate of MEN-1 mutation.
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