neuroendocrine tumours of the small bowel are the most common type of malignant neoplasm in the small intestine , accounting for 35% of small intestinal cancers [ 1 , 2 ] . small bowel neuroendocrine tumours ( nets ) are the most common type of gastrointestinal neuroendocrine tumours . the incidence and prevalence of these tumours are on the rise , as demonstrated in the surveillance epidemiology and end results ( seer ) data and the population - based study in norway [ 2 , 4 ] . a threefold increase in incidence has been demonstrated in the usa between 1973 and 2002 . the majority of these tumours do not cause carcinoid syndrome , often presenting late with metastatic disease . patients with non - hormone secreting tumours often present with vague symptoms , including intermittent abdominal pain or weight loss . a number of patients are identified coincidentally . approximately 40% of patients with metastatic disease at presentation have functionally active tumours leading to the development of carcinoid syndrome [ 710 ] . small bowel nets were generally thought to be indolent tumours ; however , their behaviour is more heterogeneous , and consequently a staging and grading system has been introduced by european neuroendocrine tumour society ( enets ) to help clinicians to optimize the management of these patients . the enets grading system incorporates ki67 index and mitotic rate to grade tumours ; these parameters had not previously been incorporated to the who 2000 classification of nets . yao et al . demonstrated a median survival from presentation of 65 months for patients with stage 4 ( distant metastatic ) well to moderately differentiated small bowel nets . more recent studies have demonstrated 5-year survival of > 70% for patients with metastatic small bowel nets [ 12 , 13 ] . a number of studies have assessed the survival benefit of primary tumour resection and other therapeutic interventions [ 12 , 1417 ] . however , there is still no consensus as to whether primary resection in patients with distal metastatic disease at presentation is beneficial . there is conflicting evidence regarding the survival benefit of liver resection , though it is generally recommended to offer liver resection if complete tumour removal or debulking of > 90% of the liver disease is possible .   to date there is limited data regarding the prognostic relevance of the proposed enets tnm staging and grading system , which has been validated in foregut and a combined study of mid - and hindgut nets [ 13 , 19 ] . in this study we report our experience with small bowel nets over a 20-year period ( from 1990 to 2010 ) . the aims of this study were twofold : firstly to determine whether the enets tnm staging system predicts prognosis in patients with small bowel nets and secondly , to determine prognostic clinicopathological factors in patients with small bowel nets . patients with small bowel primary nets were identified through a search on the neuroendocrine tumour database at king 's college hospital , london , uk . patients with tumours arising from the ampulla of vater and ileocaecal valve were excluded from analysis . site of primary and assessment of metastatic disease were based on operative , cross - sectional , and/or nuclear medicine imaging . data collection was performed by two investigators ( r. srirajaskanthan and a. ahmed ) using a specifically designed database ( filemaker pro ) . cases histological diagnosis was based on the microscopy and when possible immunohistochemical staining with net markers . a second histological assessment was performed at king 's college hospital when possible to confirm accurate histological characterisation and grading of tumours . the tnm staging system proposed by enets was used to stage patients in whom complete histological and radiological assessment was possible [ 11 , 21 ] . radiological assessment included a ct of chest , abdomen , and pelvis plus an octreotide scan in all cases . mibg scans were performed in some instances . due to the small number of patients with stage 2a disease and stage 2b disease , the histological assessment for tumour grade using the proposed enets classification was performed in all cases where histology was available . grade 1 is classified as a ki67 2% , grade 2 ki67 320% , and grade 3 ki67 > 20% [ 11 , 21 ] . patients underwent a number of therapeutic interventions in this study including surgery and biotherapy with somatostatin analogues . peptide receptor targeted therapy in this study comprised of both yttrium - dotatate therapy and since 2008 lu - dotatate therapy . selective internal radiation therapy ( sirt ) was performed on carefully selected individuals ; a treatment was regarded as embolization of one lobe of the liver . therefore , if patients had both lobes treated , this would be regarded as two treatments . table 2 illustrates the number of different therapeutic interventions patients underwent during the course of their treatment . continuous variables are reported as mean  sd or median ( range ) if not normally distributed . histological grade was assessed in univariate analysis but was excluded from multivariate analysis due to the amount of censored data leading to insufficient numbers to perform multivariate analysis . variables were removed stepwise from the model when p value exceeded 0.10 and variables with a p < 0.05 in the final model were considered significant predictors of death . data analysis was performed using graphpad prism software ( graphpad prism version 5.00 for windows , graphpad software , san diego california usa , http://www.graphpad.com/ ) and spss v.16 ( spss inc . ) . the median age of the 138 patients was 65 years ( range 2987 ) at time of diagnosis ; there were 68 males and 70 females . the 76 patients ( 55% ) had functional tumours , and the remainder were nonfunctional tumours . one hundred patients had the primary tumour resected , and 48 liver surgeries were performed in 37 patients . complete histological analysis was available in 76 cases , all of which were either g1 or g2 tumours . the remaining cases were all histologically confirmed neuroendocrine tumours ; however , ki67 analysis was not available in these cases . primary tumour resection was defined as resection of the primary tumour and if surgically possible resection of associated mesenteric mass and lymph node disease . not all primary resections were performed at the centre ; however , histological assessment of the resected specimen was performed at king 's college hospital in these cases . one hundred patients had the primary resected , and 4 patients had attempted resection of the primary but at laparotomy were found to be irresectable ; there were no postoperative deaths within 30 days of surgery . kaplan - meier curves were constructed to determine if there was any survival benefit for patients in whom the primary tumour was resected ( figure 1(a ) ) . there was improved survival in patients who underwent resection of primary tumour compared to those in whom the primary remained ( 120 versus 56 months , p < 0.05 ) . there was survival benefit in resection of the primary tumour in patients with stage 4 disease at the presentation compared to those in whom the primary was not resected ( 105 versus 56 months , p < 0.05 ) .   of patients that did not undergo resection of the primary tumour the reasons were as follows : 9 cases were due to the primary being regarded as irresectable ; 4 patients had attempted resection , however , at laparotomy the primary could not be removed ; and 2 were due to not being considered for primary resection due to comorbidity . in one case the patient declined to surgery opting for conservative management . in the remaining cases surgery was not considered for the primary due to the volume of metastatic disease and/or impaired functional status due to carcinoid heart disease . thirty - seven patients had a total of 48 liver resection surgeries , including 2 patients who had a liver transplant . the median age of patients undergoing liver resection was 55 years ( range 3277 ) . all patients that underwent liver resection had the primary tumour resected previously or at the time of liver surgery . of the 37 patients undergoing liver surgery 14 patients also had the primary removed at the time of surgery . 1 patient had a postoperative - bleed , 1 bile leak , and 1 wound infection which required drainage . two patients underwent liver transplant during this study : one patient died 5 months following the surgery , due to development of pneumonia , and the other patient remains disease - free at 240 months posttransplant . there was a significant survival benefit in patients who underwent liver resection of hepatic metastases with stage 4 small bowel nets compared to patients with stage 4 small bowel nets and hepatic metastases who did not have liver resection ( 128 versus 76 months , p < 0.05 ) , figure 1(b ) .   on univariate analysis , the following clinicopathological features were related to improved prognosis : not having carcinoid heart disease , resection of primary tumour , g1 histological grade , and liver resection . there was no difference in survival for the following factors : gender , uptake on octreoscan , presence of a functional syndrome , and treatment with somatostatin analogues . multivariate analysis was performed using cox regression analysis adjusting for all factors that showed a significant difference on univariate analysis . primary tumour resection and no carcinoid heart disease were identified as the only independent predictors of survival . not having the primary tumour resected was associated with a relative risk of 2.9 ( 1.36.1 ) , p < 0.005 . not having carcinoid heart disease was associated with a decreased relative risk 0.145 ( 0.060.36 ) , p < 0.005 . the tnm staging demonstrated significant difference in survival between stage 2 and 3 versus stage 4 disease ( p < 0.05 ) and also stage 3 versus stage 4 disease ( p < 0.05 ) . there was no significance in survival between stage 2 and stage 3 disease ( figure 2(a ) ) . therefore , improved survival in patients with localised / locoregional disease compared to patients with metastatic disease at the presentation was demonstrated . there was significantly improved prognosis between g1 compared to g2 tumours , p < 0.05 . there were no patients with g3 tumours for assessment , see figure 2(b ) . there were 4 patients with tnm stage 2 disease , 23 patients with tnm stage 3 disease , and 10 patients in whom the staging was not known but had no evidence of residual disease postoperatively and were regarded as r0/r1 resection . the remaining patients had clear evidence of distant metastatic disease prior to undergoing resection of the primary tumour .   of the patients who underwent attempted curative resection without distal metastatic disease there was no recurrence in patients with stage 2 disease , and median duration of followup was 37 months ( 17180 months ) . median followup for patients with stage 3 disease was 37.5 months ( range 6119 months ) . recurrence occurred in 7 of 23 ( 30.4% ) patients , and median duration to recurrence was 47 months ( range 1196 months ) . the 5-year and 10-year survivals were 79.5% and 48.5% , respectively , for all patients independent of the stage of the disease . the median survival for patients with stage 4 disease was 98 months , with 5-year survival of 74.5% . there were 44 ( 32.8% ) deaths during the follow - up period of the study . 20.5% of patients died from nontumour - related deaths ; the most common causes were cardiovascular death and a second malignancy . we have demonstrated that the enets tnm staging system for midgut offers prognostic information , with the worst survival demonstrated in patients with stage 4 disease compared with stage 2 or stage 3 disease . furthermore , the proposed grading system based on ki67 and mitotic index provided statistically different prognosis between g1 and g2 nets .   no difference in survival was demonstrated between stage 2 and stage 3 disease ; this could be in part due to the duration of followup and small numbers of cases with stage 2 disease . however , other studies have not demonstrated difference in survival between stage 2 and stage 3 disease . markers of cellular proliferation as measured by ki67 index and mitotic rate were incorporated in to the novel enets tnm staging and grading system . studies demonstrated these markers as predictors of survival in pancreatic and upper gastrointestinal nets and hence their incorporation into the enets guidance [ 11 , 22 , 23 ] . in this study we demonstrated significant improvement in survival for patients with g1 compared to those with g2 nets ; this supports the findings in other studies [ 14 , 24 ] . overall the 5-year and 10-year survivals were 79.5% and 48.5% , respectively , for all patients independent of stage of disease . this shows improvement in the 5-year survival when compared to previous studies , including the seer data . there appears to be a trend towards improvement in survival when looking at the 5-year survival data from recently published data looking at patient cohorts over the last two decades [ 6 , 12 , 14 ] . it may be in part related to increased use of somatostatin analogues and their antiproliferative effect . secondly , the management of patients in multidisciplinary teams and the more aggressive surgical management of these patients may have improved survival . the study cohort may be biased as it is not a population - based survival but instead a survival of patients managed in a specialist centre . finally , lead time bias may also be a factor ; however , there is no clear evidence to support that patients are being diagnosed at an earlier stage of the disease . the cause of death in this study demonstrated that 47.3% were related to tumour progression which is similar to that published in the ukinets study . a similar percentage of patients died from carcinoid heart disease and small bowel obstruction [ 14 , 2527 ] . interestingly 20.5% of patients died from tumour - unrelated causes , which is similar to that identified from previous studies [ 14 , 28 ] ; in part it could be related to the longer survival of patients with small bowel nets , leading to other causes of death accounting to a large percentage of deaths . this study demonstrates improved survival in patients in whom the primary tumour was resected , with univariate and multivariate analyses . furthermore , there was improved survival for patients who presented with stage 4 disease who had resection of primary tumour compared to those in whom the primary was not resected . previous studies have demonstrated a survival benefit in resection of primary tumour ; however , the study population has been rather heterogenous . a recent systematic review by capurso et al .   concluded that there is a possible benefit of resection of the primary lesion in patients with unresectable liver metastases . this study demonstrates significant prognostic benefit of liver resection on survival using univariate analysis , though this is not a prognostic factor with multivariate analysis . numerous studies have demonstrated improved symptom control and quality of life following hepatic resection and tumour debulking [ 22 , 3032 ] . the role of hepatic surgery in patients with metastatic nets should still be considered in appropriate candidates [ 14 , 18 ] . a number of studies have demonstrated improved prognosis following liver resection in patients with small bowel nets in a univariate analysis [ 14 , 16 , 33 ] . there is limited data regarding the time to develop recurrent disease following  curative resection  in patients with local / locoregional disease . following what was regarded as r0/r1 resection we have demonstrated that median time to development of recurrence is 55 months . approximately 30% of patients with stage 3 disease will develop recurrence within a median period of 47 months . studies by le roux and landerholm have demonstrated recurrence rates around 30% following complete resection of primary tumour and locoregional disease [ 28 , 34 ] . followup of patients with stage 2 or 3 tumours should be extended beyond 5 years . this study is a single centre experience that has certain inherent limitations ; due to the nature of referrals it was not possible to accurately stage all patients who underwent surgical resection and perform complete histological analysis . the rate of disease recurrence following resection of locoregional disease may be overestimated due to referral bias ; however , similar rates have been reported in other studies . this study has demonstrated that enets tnm staging and grading system is able to prognosticate between stage of disease and grade of tumour . primary tumour resection and not having a carcinoid heart disease there may potentially be a role of determining the likelihood of recurrence following surgery using the tnm staging system .
introduction . 
 small bowel neuroendocrine tumours ( nets ) are the most common type of gastrointestinal neuroendocrine tumours . 
 the incidence and prevalence of these tumours are on the rise . 
 the aims of this study were to determine prognostic clinicopathological features and whether the enets tnm staging system predicts prognosis and also . method . 
 clinical data was collected retrospectively from 138 patients with histologically proven small bowel nets managed at king 's college hospital . 
 histology was reviewed and small bowels tumours , were staged according to the enets tnm staging system . results . 
 median age was 65 years ( range 2987 ) . 
 the 5-year survival was 79.5% and the 10-year survival was 48.5% . 
 resection of the primary tumour was associated with improved survival ( 120 versus 56 months , p < 0.05 ) . 
 on multivariate analysis prognostic factors were primary tumour resection and not having a carcinoid heart disease . 
 tnm staging significantly separated survival of stage 2 and stage 3 from stage 4 nets . conclusion . 
 small bowel primary tumour resection and not having carcinoid heart disease are prognostic factors . the enets tnm staging and grading system appears to be of prognostic relevance to small bowel nets .