Novelties in Primary and Metastatic GEP-NENs Clinical Outcome Investigation

Introduction: Gastro-entero-pancreatic neuroendocrine neoplasms (GEP- NENs) WHO classification, using strict cut-offs, should reflect their biological features. In real world, strict cut-offs not adequately segregate prognostic groups, in particular on metastasis (M). Aim(s): To investigate GEP-NENs clinical outcome in primary tumors (T) and M. Materials and methods: 264 patients from 3 Italian centers were analyzed regarding: morphology, mitoses and Ki67 considering both in T, lymph node (N) and M. Ki67 and mitoses were studied both as WHO cut-offs (namely Ki67 LI – MI) and in continuous scale (namely Ki67-Mitoses). Clinical endpoints were overall survival (OS) and relapse-free survival (RFS). With same aim T stage, N, and tumor deposits (TD) were considered. Results: Ki67 LI (HR 1.16, 95% CI 1.11-1.22, p<.0001) and MI (HR 1.08, 95% CI 1.06-1.10, p<.0001) remained the strongest OS predictors. Patients were divided into 3 groups according to origin: ileum/jejunum (Group 1), pancreas (Group 2) and all other sites (Group 3). Group 3 showed worse RFS (HR 1.94, 95% CI 1.19-3.16, p=.008). The continuous scale was more reliable to predict RFS (HR 1.11, 95% CI 1.08-1.14, p<.0001 for a 5-point increase in Ki67 and HR 1.05, 95% CI 1.04-1.07, p<.0001 for 1 mitotes point increase, for the combination of all three groups) compared to the current cut- offs. At multivariable analysis, Ki67 (HR 1.14, 95% CI 1.06-1.22, p=.0006), TD (HR 4.70, 95% CI 3.17-6.98, p<.0001) and pancreatic origin (HR 1.50, 95% CI 1.01-2.21, p=0.04 compared to group 1), were the best RFS predictor. Conclusion: Ki67 LI and MI were the strongest OS predictors. Moreover, RFS could be better predicted by continuous scales mode in both Mitoses and Ki-67 and by TD study.