Gastric Carcinoma with Exocrine and Neuroendocrine Components: A 16-Year Cohort Analysis and International Comparison

Background: Gastric carcinoma with coexisting exocrine and neuroendocrine components (GC-EN) is rare and clinically aggressive, but its temporal pattern and prognostic impact remain poorly characterized. Materials and Methods: We retrospectively analyzed 1043 patients who underwent curative gastrectomy at our center between 2008 and 2024. Following tumor-node-metastasis staging and 1:2 pTNM stage matching, 882 patients were included; 294 had GC-EN, of which 175 had GNEC, and 588 had GC. Clinicopathological characteristics were compared, survival outcomes were assessed using Kaplan-Meier estimates and multivariate Cox regression, and the proportion of GNEC cases in our center and the U.S. surveillance, epidemiology, and end results (SEER) database were evaluated. Survival patterns of GNEC were further compared with published international cohorts using Engauge Digitizer software. Results: Among the patients with gastric cancer admitted for treatment, the proportion of NEC fluctuated between 4.01% and 4.38% (2008-2013) and finally dropped to 1.6% (2020-2021), whereas the SEER database showed a modest rise with a late dip (1.67% → 2.72% → 2.44%). The overall survival (OS) of patients with NEC appeared to improve at our center (1-/2-/3-year OS: 85.1%/59.6%/34% in 2008-2012 to 94.1%/87.5%/76.2% in 2021-2024), whereas that in the SEER database declined over the same periods. The 5-year OS of the two databases remained similar (42.7% vs. 41.0%). The 1, 2 and 5-year survival rates of NEC in the external cohorts were higher than those in the SEER and Berlin series; however, the 3-year survival rates were similar, with the Italian multicenter cohort performing the worst. The Kaplan-Meier analysis demonstrated significantly worse OS for GC-EN versus GC (p < 0.001); within GC-EN, the NEC subgroup (NEC ≥ 70%) had the poorest outcomes (p < 0.001), whereas mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) and adenocarcinoma-dominant (AC-dominant) cases had similar outcomes as GC (p = 0.52, p = 0.81). In the multivariable Cox model, GC-EN histology remained independently associated with worse OS (HR = 1.49, 95% CI 1.15-1.92; p < 0.01). Metastatic lymph node burden and higher pTNM stage were associated with worse survival, whereas greater lymph node retrieval and age 40-65 years were protective. After adjustment, vascular invasion, tumor size, and location were not independently significant. Conclusions: Over the past 16 years at the National Cancer Center of China, the proportion of NEC cases decreased, and survival appeared to improve. NEC-dominant disease appeared to be the main driver of poor prognosis within GC-EN, whereas MiNEN and AC-dominant tumors showed survival patterns similar to GC in this cohort. These findings emphasize the need for GC-EN-specific risk stratification and tailored treatment strategies.