Clinicopathological Spectrum and Survival in Esophageal Neuroendocrine Carcinoma and Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms: A 74-Patient Cohort

Background: Primary esophageal neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are rare malignancies with a poor prognosis. Data on clinicopathological features and survival outcomes in Central China are still limited. Methods: We retrospectively analyzed 74 patients with pathologically confirmed untreated primary esophageal NEC/MiNEN between January 2014 and June 2024. Neuroendocrine and non-neuroendocrine components were evaluated using immunohistochemical staining. The primary outcome was overall survival (OS), which was analyzed using the Kaplan-Meier method and Cox regression. Results: Among 74 patients with pathologically confirmed primary esophageal NEC/MiNEN, 95.9% had irregular masses with surface erosion or ulcers. 56 patients had small-cell NEC, of whom 16 had adenocarcinoma/squamous cell carcinoma. Eighteen patients had large-cell NEC, including 12 patients with adenocarcinoma/squamous cell carcinoma. Immunohistochemistry showed high positivity for CD56 (98.6%), synaptophysin (Syn, 95.8%), and insulinoma-associated protein 1 (INSM1, 88.5%), but lower for chromogranin A (CgA, 56.9%). Survival analysis showed that there was a significant difference in OS between patients with limited disease (LD, limited to the primary site with regional lymph nodes) and those with extensive disease (ED, with distant metastasis) (58 months vs 9.0 months, P < 0.001). The OS of patients with MiNEN was significantly longer than that of patients with pure NEC (76 months vs 23 months, P < 0.001), while there was no significant difference in OS between patients with large-cell neuroendocrine carcinoma (LCNEC) and small-cell neuroendocrine carcinoma (SCNEC) ( P = 0.095). The independent predictors of poor survival were organ metastasis (Hazard Ratio (HR)=3.774, P =0.003) and lymph node metastasis (HR=4.569, P =0.002). Conclusion: This study confirms that disease stage (LD vs ED) is one of the most important prognostic determinants of esophageal NEC/MiNEN, and organ and lymph node metastases are independent predictors of poor survival. The findings of this study contribute to improving the predictive efficacy of the prognosis of patients with NEC. Keywords: esophageal, neuroendocrine carcinoma, MiNEN, immunohistochemistry, treatment, prognosis