Second primary malignancies in neuroendocrine tumors: a single-center cohort study

Improved survival among patients with neuroendocrine tumors (NETs), has increased attention to long-term oncologic outcomes, including second primary tumors (SPTs). However, their clinical patterns and timing remain incompletely characterized. In this retrospective single-center cohort study, we analyzed 201 patients with NETs diagnosed between 2005 and 2023. SPTs were defined according to Warren-Gates criteria and classified as synchronous (≤6 months) or metachronous (>6 months). Standardized incidence ratios were calculated using national cancer registry data. Predictors of SPT occurrence were explored using regression and competing-risk models. Thirty-five patients (17.4%) developed an additional malignancy. Patients with SPTs were older at NET diagnosis (median: 65 vs. 58 years; P = 0.006), while most other clinicopathological characteristics were similar. The most frequent SPTs were colorectal (26%), genitourinary (20%), and breast cancers (11%). SPTs were synchronous (71%), whereas metachronous tumors occurred at a median of 4.9 years after NET diagnosis. Standardized incidence ratios suggested an increased occurrence of colorectal, melanoma, and breast cancers, but estimates were imprecise because of limited event numbers. Older age at NET diagnosis independently predicted SPT occurrence (odds ratio: 1.62 per SD; 95% confidence interval: 1.07-2.54; P = 0.021), while no other variable reached statistical significance. Competing-risk analysis demonstrated metachronous SPTs of approximately 5-6% at 5 years and 7.5% at 10 years. Approximately one in six patients developed an additional malignancy, most frequently detected synchronously. Diagnostic intensity during initial staging may contribute to SPT detection, while long-term risk of metachronous tumors persists. These results support individualized follow-up with attention to gastrointestinal and site-specific cancer surveillance.