Clinicopathological And Survival Analysis Of Small Intestinal Neuroendocrine Tumors-A Population Based Retrospective Study

Neuroendocrine tumors(NETs)are heterogeneous,slow-growing malignant tumors with a low incidence.The incidence of NETs has increased significantly over the past decades,partially due to the increased use of endoscopic and cross-sectional image techniques as well as the improved recognition of neuroendocrine histology.Previous studies were limited for it is impossible to accumulate an adequate number of patients with this rare disease from a single center in a brief period of time to examining clinicopathologic features as well as survival outcomes.Therefore,using a large,nationwide,population-based SEER database,we performed a retrospective analysis to define survival outcomes of SiNETs.Purpose:We aimed to explore the clinicopathological characteristics,the survival outcomes impacts of surgical intervention of small intestinal neuroendocrine tumors.We further refine a new N classification for updated TNM stage.Methods:A retrospective cohort study was conducted by using data from the Surveillance,Epidemiology,and End Results(SEER)database.Clinicopathologic features were analyzed in patients diagnosed with SiNETs between 2000 to 2012.The cancer specific survival(CSS)was calculated by the Kaplan-Meier method.Multivariable Cox regression models with hazard ratios(HRs)were constructed to analyze survival outcomes and risk factors.Using the X-tile program,we calculated an optimal cut-off value for lymph node ratio(LNR)and proposed a novel Nr category:Nr0,0%;Nr1,1%-60%;Nr2,60%-100%.Adjusted hazard ratio and cluster analysis(k-means clustering)were performed to differentiate TNrM stages.Results:The adjusted incidence of SiNETs is approximately 1.3/100,000.Tumors are most commonly located in the ileum and are small(? 2 cm).The 5-year and 10-year CSS rates were 95.0%and 88.5%,respectively.Age>50 years,large tumor size(>2cm),poor differentiation,advanced T classification,and absence of surgical treatment were independent predictors of poor survival.Stratified analysis indicated that surgery significantly improved survival in patients that were white(HR,0.45;95%CI,0.31-0.66),>50 years old(HR,0.61;95%CI,0.42-0.88),had duodenal tumors(HR,0.43;95%CI,0.25-0.76),large tumors(>2cm)(HR,0.32;95%CI,0.14-0.73),advanced T classification(T3:HR,0.29;95%CI,0.11-0.79;T4:HR,0.18;95%CI,0.09-0.39)or well differentiation(HR,0.55;95%CI,0.37-0.83).There was no significant survival difference between local resection and radical resection(P =0.884).Patients with existing TNM stage ? and ? had equivalent survival prognosis(P= 0.214).Current N classification was not a significant predictor of patient survival(P=0.264).Multivariate analyses identified the revised Nr classification,based on LNR of 0.6 optimal cut-off value,as an independent prognostic factor(Nr0:refernce;Nrl:HR 1.290,95%CI,0.709-2.346,P=0.403;Nr2:HR2.285,95%CI 1.154-4.525,P=0.018).By incorporating the Nr classification,a revised TNrM which categorized patients into three new stage was proposed as stage I(T1-2Nr0-1),stage ?(T3Nr0-1)and stage III(TxNr2 or T4Nrx).TNrM stage had better stratification according to the survival outcome(stage I:reference,stage II:II:HR 3.852,95%CI 1.731-8.575,P=0.001;stage?:HR 7.169,95%CI 3.220-15.963,P<0.001).Conclusion:1.The incidence of SiNETs increases gradually and have a favorable prognosis.Tumors are commonly located in the ileum and are small(? 2 cm).2.Surgical resection may improve outcomes,particularly in older patients and those with large tumors.More aggressive resections couldn't improve outcomes.3.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.