The Lymph Node Ratio Optimizes Staging in Patients with Small Intestinal Neuroendocrine Tumors

Background: The effectiveness of the current Tumor, Lymph node, Metastases (TNM) staging system in small intestinal neuroendocrine tumors (SiNETs) is unsatisfactory. Current N classification only distinguishes between node-negative and node-positive status. We aim to refine the N classification for updated TNM stage.

Methods: During the period from 1988 to 2012, patients with non-metastatic -SiNETs were enrolled in the Surveillance, Epidemiology, and End Results database. Using the X-tile program, we calculated an optimal cutoff value for lymph node ratio (LNR) and proposed a novel Nr category. Survival outcomes were estimated using the Kaplan-Meier method and Cox regression model. Adjusted hazard ratio (HR) and cluster analysis were performed to differentiate TNrM stages.

Results: Patients with existing TNM stage I and II had equivalent survival prognosis (p = 0.214). Current N classification was not a significant predictor of patient survival (p = 0.372). Multivariate analyses identified the revised Nr classification, based on LNR of 0.6 optimal cutoff value, as an independent prognostic factor (p = 0.020). By incorporating the Nr classification, a revised TNrM, which categorized patients into 3 new stages was proposed: stage I (T1-2Nr0-1), stage II (T3Nr0-1), and stage III (TxNr2 or T4Nrx). TNrM stage had better stratification according to the survival outcome (primary cohort: stage I: reference, II: HR 3.852, 95% CI 1.731-8.575; III: HR 7.169, 95% CI 3.220-15.963, p < 0.001; validation cohort: stage I: reference, II: HR 2.034; III: HR 3.815; p < 0.001).

Conclusions: The Nr classification more accurately stratifies SiNET patients than current N classification. The new TNrM staging system could improve the ability to predict survival outcome of SiNET patients.