Background: Appendiceal cancer (AC) survival rates have improved over the last decade. The risk of second primary malignancy (SPM) in AC survivors has become an important concern. Therefore, this study aimed to estimate the risk of SPM in patients with primary AC. Methods: We performed a retrospective cohort study of patients ≥18 years of age diagnosed with AC between 2000-2016 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. The study endpoint was the occurrence of SPM diagnosed after two months of the index AC. We calculated the standardized incidence ratio (SIR) with 95% confidence intervals (CI) for SPM in AC survivors by using the SEER software. Results: Of 9578 patients with AC, 598 (6.2%) developed a SPM. The overall risk of SPM for all sites was significantly increased in AC patients (SIR = 1.46, 95% CI 1.34-1.58). The highest risk of developing a SPM was seen in ages < 60 years, females, and Asian/Pacific Islanders, respectively (SIR = 1.84, 95% CI 1.64-2.07; SIR = 1.55, 95% CI 1.38-1.74; SIR = 1.72, 95% CI 1.12-2.52). The SPM sites associated with increased incidences included the small intestine, followed by the appendix, splenic flexure of the colon, and peritoneum/omentum/mesentery. There was an increased risk of developing non-Hodgkin lymphoma, but no elevated risk with developing second leukemias. Surgery and chemotherapy were associated with an increased incidence risk of SPM, respectively (SIR = 1.45, 95% CI 1.33-1.57; SIR = 1.47, 95% CI 1.25-1.71). Conclusions: AC survivors have an increased incidence of developing SPM, most notably in the small intestine, which suggests a pathophysiological process affecting derivatives of similar embryological origin. Long-term surveillance for SPM is recommended for AC survivors, especially those at high risk.

*Excess risk is per 10,000.