Ampullary Neuroendocrine Tumors: Multicenter Experience and Emerging Perspectives on Endoscopic Treatment

BACKGROUND: Ampullary neuroendocrine tumors (NETs) are extremely rare, representing 0.3%-1% of gastrointestinal NETs and less than 2% of periampullary cancers. Due to their rarity, there is limited data on their natural history, management, and outcomes. Current European Neuroendocrine Tumor Society guidelines (2023) recommend pancreaticoduodenectomy (PD) as the standard treatment. However, this approach is invasive and associated with high morbidity and mortality. Emerging evidence suggests that endoscopic papillectomy (EP) could be a viable alternative in selected cases. This retrospective multicenter study aimed to evaluate the feasibility and outcomes of endoscopic resection for ampullary NETs. METHODS: This retrospective case series included 14 patients who underwent EP for ampullary NETs between 2011 and 2022 across three Italian tertiary centers. Pre-procedural evaluation was performed following European Society of Gastrointestinal Endoscopy guidelines. Endoscopic papillectomy was performed under monitored sedation, using standard snares for en bloc resection. Follow-up endoscopy was conducted at a median of 3 months. Primary outcomes included complete resection (R0) and recurrence rates; secondary outcomes focused on adverse events. RESULTS: Fourteen patients (median age: 62.5 years; 50% male) were included. Median tumor size was 18 mm. In 12 out of 14 cases, ampullary NETs were diagnosed only after endoscopic resection. Post-resection histology identified 8 G1 NETs (Ki-67 1%) and 6 G2 NETs (Ki-67 5%). Complete resection was achieved in 11 cases (78.6%). Among 3 incomplete resections, 2 were managed surgically, while 1 was followed up without recurrence. Residual disease was detected in 3 patients: 2 were managed endoscopically, and 1 required surgery. No recurrences occurred during a median follow-up of 14.5 months. Adverse events occurred in 42.9% of patients, including 5 cases of bleeding and 1 case of mild pancreatitis, all resolved without major sequelae. Median hospital stay was 2.5 days. CONCLUSIONS: Our findings suggest that EP offers a promising alternative to surgery in selected patients with ampullary NETs. Endoscopic resection was associated with high rates of R0 and favorable short-term outcomes, with effective endoscopic management of residual disease and procedure-related adverse events. Consistent post-procedural surveillance remains essential to detect residual or recurrent disease. Larger prospective studies are warranted to refine patient selection criteria, optimize protocols, and establish the long-term efficacy.