Clinicopathologic and Molecular Characteristics of Gastric Cancer With a Neuroendocrine Carcinoma Component

Gastric cancers containing a neuroendocrine carcinoma (NEC) component show aggressive clinical behavior, but the clinicopathological significance of NEC components and the mechanisms associated with neuroendocrine differentiation (NED) remain incompletely understood. This study evaluated the prognostic, metastatic, molecular, and immune features of gastric cancers with NEC components.

This retrospective cohort study included patients with resectable gastric adenocarcinoma (GAC) and gastric adeno-neuroendocrine carcinoma (G-ANEC) treated at Peking University Third Hospital from 2011 to 2022. Clinicopathological characteristics, recurrence patterns, lymph node metastatic components, and survival outcomes were analyzed. Propensity score matching (PSM) was performed at a 1:3 ratio to reduce baseline imbalance. Component-level immunohistochemistry was used to compare adenocarcinoma (ADC) and NEC components. Transcriptomic data from TCGA-STAD were analyzed to explore pathways associated with ASCL1 expression and STAT3 pathway activity. ASCL1-overexpressing AGS gastric cancer cells were established, and invasive capacity was assessed using Transwell invasion assays.

Among 666 patients, including 639 with GAC and 27 with G-ANEC, G-ANEC showed more aggressive clinicopathological features than conventional GAC. After PSM, G-ANEC was associated with worse overall survival (OS) and recurrence-free survival (RFS). Recurrence and liver metastasis rates were significantly higher in G-ANEC than in GAC. Component-level analysis showed that lymph node metastases in G-MANEC were predominantly composed of NEC components, indicating NEC enrichment in metastatic deposits. ASCL1 and p-STAT3 expression were significantly higher in NEC components than in paired ADC components (P = 0.041 and P = 0.016, respectively). TCGA-STAD analyses showed that high ASCL1 expression and increased STAT3 pathway activity were associated with neuroendocrine-related pathway enrichment, reduced immune-related pathway activity, and poorer survival. CD8+ T-cell infiltration was lower in NEC components than in ADC components (P < 0.001) and inversely correlated with ASCL1 expression (rpb = -0.645, P = 0.006). In vitro, ASCL1-overexpressing AGS cells showed enhanced invasive capacity.

Gastric cancers containing NEC components are associated with aggressive clinicopathological behavior, increased recurrence, and worse prognosis. ASCL1 and STAT3 are associated with NED and immune suppression, and ASCL1 overexpression enhances gastric cancer cell invasion in vitro. These findings suggest that NEC component-associated molecular and immune features may contribute to the aggressive phenotype of G-ANEC and support distinct therapeutic considerations beyond conventional GAC.