Real-world presentation and outcomes of gastroenteropancreatic neuroendocrine neoplasms in Italy: findings from the nationwide Itanet prospective database

Background: The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is increasing, but population registries seldom capture detailed clinical data. The Italian Association for Neuroendocrine Tumours (Itanet) established a nationwide prospective database to describe presentation, diagnostic pathways, management, and outcomes of newly diagnosed GEP-NENs in Italy. Methods: This multicentre prospective observational study enrolled 2138 consecutive patients with newly diagnosed GEP-NENs across 38 Italian centres (2019-2024). Clinical, pathological, imaging, and treatment data were prospectively collected and centrally validated. Descriptive and survival analyses were performed; Ki-67 was modelled as a continuous variable. Findings: Median age was 60.6 years, and 55.9% (1195/2138) were male. Tumours were well-differentiated NETs in 90.8% of patients (1942/2138), mainly of pancreatic (41.4%, 886/2138) or ileal (19.7%, 422/2138) origin. Median Ki-67 was 2%. An incidental diagnosis occurred in 58.6% (1254/2138) of cases. Among symptomatic patients, the mean diagnostic delay was 197 days (224 for pancreatic vs 184 for small bowel; p = 0.039). 68Ga-DOTA-peptide PET showed higher diagnostic yield than CT or MRI in small-bowel primaries (93.7% vs 83.1% vs 67.4%), whereas performance was similar in pancreatic tumours. Data on first-line treatment were available for 2050 patients. Initial management included surgery in 36.4% (746/2050), watchful waiting in 19.7% (404/2050), endoscopic resection in 7.7% (158/2050). Overall, 30.6% (627/2050) of patients received systemic therapy, most commonly somatostatin analogues in 23.7% (487/2050). Over a median follow-up of 271 days (IQR 121-530), 62 deaths were observed (event rate 4.9%). Overall survival differed markedly according to metastatic status and tumour grade. Ki-67 was prognostic when modelled continuously (p < 0.001), and a 15% cutoff identified poorer outcomes. Interpretation: This nationwide prospective study delineates real-world diagnostic and therapeutic patterns of GEP-NENs in Italy, confirms Ki-67 as a continuous prognostic biomarker, and identifies a 15% threshold associated with worse survival, providing a benchmark for outcome assessment and future clinical research. Funding: None.