Esophageal neuroendocrine carcinoma: molecular insights, diagnostic advances, and emerging treatment strategies

Esophageal neuroendocrine carcinoma (ENEC) is a rare and aggressive malignancy, characterized by its high-grade, poorly differentiated nature. Despite advancements in understanding neuroendocrine tumors (NETs), ENEC remains an under-researched and poorly understood entity, presenting significant challenges in both diagnosis and treatment. Molecular studies have revealed frequent mutations in TP53 and RB1, along with genetic profiles paralleling small cell lung cancer (SCLC), suggesting shared oncogenic pathways that may guide targeted therapeutic approaches. However, the rarity of ENEC has limited the development of standardized treatment regimens, with most strategies borrowed from other malignancies such as SCLC. Current treatments, including platinum-based chemotherapy, show moderate success, yet response rates remain variable, particularly in advanced stages. The role of immunotherapy and targeted therapies is under investigation, with promising case reports but limited clinical evidence. Emerging diagnostic technologies, such as molecular profiling and liquid biopsy, offer enhanced precision in early detection and personalized treatment plans. Prognostic factors, such as Ki-67 proliferation index, serum biomarkers, and tumor stage, have shown significant associations with survival outcomes, though they remain under-explored in prospective clinical trials. Given the unique molecular features of ENEC, including high tumor mutational burden and distinct immune profiles, further research is essential to develop effective biomarkers, refine prognostic models, and create personalized, targeted therapies. This review aims to consolidate current knowledge on ENEC’s molecular biology, diagnosis, and treatment, while identifying gaps in research and suggesting directions for future investigation to improve patient outcomes.