893 Assessing the Validity of Staging Classification for Small Intestinal Neuroendocrine Tumors
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AGA Abstracts of NleH1 in WT EPEC (WT EPEC+pNleH1) increased survival at 12d to 94%. Protection of wt loss was significantly better with NleH1 than 2 (Fig 1). Colon length was also improved by EPEC expressing NleH1 (7.3±1.5 and 6.8±1.2 cm, WT+pNleH1 and ΔnleH1/2+pNleH1, resp; n=8) compared to ΔnleH1/2 (5.2±0.3 cm, n=4, p ,0.05). H&E staining revealed significantly decreased colonic inflammation in animals infected with bacteria expressing NleH1 or NleH2 or both. In summary, these data show that NleH1 and 2 protect against intestinal inflammation and rescue mice from DSS colitis with NleH1 being more effective than NleH2. Figure 1: Protection from DSS-induced weight loss by NleH1 and 2. 893 Assessing the Validity of Staging Classification for Small Intestinal Neuroendocrine Tumors Michelle K. Kim, Richard R. Warner, Sasan Roayaie, Noam Harpaz, Stephen C. Ward, Steven H. Itzkowitz, Juan Wisnivesky Introduction: Small intestinal neuroendocrine tumors (SI-NETs) are biologically heterogene- ous and have a variable clinical course. The neuroendocrine tumor societies have recently proposed a new TNM-based staging classification. In this study, we used data from a national population-based cancer registry to validate the ability of this new staging system to predict patient outcomes. Methods: We used the Surveillance, Epidemiology and End Results (SEER) database to identify all patients with confirmed SI-NETS diagnosed between 1988 and 2009. Information on primary tumor size, depth of tumor invasion, lymph node involvement, and presence/absence of distant metastases was used to assign TNM stage. Kaplan Meier methods were used to assess survival differences (up to 10 years from diagnosis) according to TNM status; Cox proportional hazards models were constructed to evaluate differences in prognosis after controlling for potential confounders. Results: We identified 6,792 patients with patho- logically confirmed SI-NETs and complete stage information. The mean (standard deviation) patient age was 62.4±13.3 years, 52% were male, and 74% were white. Overall, 42% was located in the ileum, 23% in the duodenum, and 6% in the jejunum. According to current staging criteria, 11%, 26%, 49%, and 14% were stage I, II, III, and IV, respectively. Kaplan Meier analysis showed increasingly worse survival with progressive higher T (T1 to T4) categories (p,0.0001). Similarly, patients with N0 (p ,0.005) and M0 (p,0.0001) disease had improved survival as compared to N1 and M1 disease, respectively. However, survival curves stratified by stage showed overlap among several categories (Figure 1). Stage I and stage IIA cancer had comparable survival (10-year survival of 97% vs. 94%). Additionally, 10 year survival for stage IIIB (79%) was better than for stage IIIA (72%). Stage IV cancer had the worst outcomes (10-year survival of 44%). Adjusted analyses showed that T3 (hazard ratio [HR]: 3.21, 95% confidence interval [CI]: 2.04-5.06) and T4 (HR: 5.33, 95% CI: 3.31- 8.58) tumors had significantly worse survival than T1 tumors after adjusting for other confounders. T2 had comparable survival (HR 1.14, 95% CI: 0.70-1.85) to T1 tumors. However, N1 disease was not associated with worse survival in the adjusted model (HR: 1.35, 95%CI: 0.86-2.10). Conclusions: While the newly proposed staging system for SI- NETs helps to predict prognosis in early and late stage disease, the classification does not discriminate well prognosis among patients with locoregional disease. Specifically, involve- ment of regional lymph nodes (N1 disease) does not appear to add independent prognostic information beyond that provided by T status. Further studies are needed to evaluate whether there are features of N1 disease that may further refine staging. Figure 1. NET cancer-specific survival according to stage. S-158 AGA Abstracts 894 The Influence of Surgical Intervention on Long-Term Outcome of Gastroenteropancreatic Neuroendocrine Tumors (NET) in a Large German Multi Center Cohort Study Ulrich-Frank Pape, Nehara Begum, Andreas Pascher, Anja Rinke, Christine Wurst, Katharina Holzer, Marianne Pavel, Thomas J. Musholt, Peter E. Goretzki, Wolfram T. Knoefel, Detlef K. Bartsch Neuroendocrine neoplasms (NEN) of the gastroenteropancreatic (GEP) system are a heteroge- neous group of malignant neplasms (including carcinoid tumors) with variable outcome and a wide spectrum of treatment options. Due to variations in tumor biology, extent of tumor disease, symptomatology and treatment modalities prediction of outcome is complex and quite variable. Particularly the results of surgery are largely cohort- and center-depepdent and therefore the German NET-registry has collected and analyzed outcome results from a large multi-centric German cohort with particular attention to influences of surgical interven- tion. Methods: 2358 patients (pts) with histologically proven NET diagnosed since 1999 from 32 centres in Germany registered in the German NET registry were retrospectively analyzed for pathological, clinical and treatment data and information on overall and NET- specific survival using Kaplan-Meier analysis and log-rank testing. Results: Primary tumor localizations were in pancreas (33%), small bowel (24%), stomach (7%), rectum (6%), appendix (4%), colon (2%), other localizations (11%) or of unknown primary tumor (13%) and 46% were already metastasized at initial diagnosis. During follow-up 16.1% of the pts died. Overall 2-, 5-, and 10- year survival rates (YSR) were 93, 82 and 66% while NET- specific 2-, 5-, and 10-YSR were 94, 85 and 70%. Survival was significantly better in patients with early tumor disease (limited disease LD, stages I-IIIA) than in extensive disease (ED, stages IIIB and IV) in both NET-G1/" and NEC-G3 (p ,0.001 for LD vs. ED in both subgroups). 1559 surgical interventions were performed, 93.6% as first-line treatment and 68.7% with curative intent. 5-YSR in operated pts (82%) was significantly better than in non-operated pts (61%, p ,0.001) in the whole cohort as well as in pts operated with curative (84%) vs. palliative (60%, p ,0.001) intent. Besides WHO-classification resection status appeared to be a statistically significant predictor of outcome with 5-YSR of 90% for R0, 82% for R1, 64% for Rx and 55% for R2-resection status after curatively intended resection of the primary tumor. Similarly, long-term success of curatively intended resection of metastases depended on R-status with 5-YSR of 90% for R0, 79% for R1, 66% for Rx and 43% for R2-resections. Conclusion: Surgical resection of primary neuroendocrine (carcinoid) tumors as well as metastases with curative intent significantly improves long- term poutcome of GEP-NEN with the resection status indicating the long-term success of surgery. Surgery should therefore always be considered in early-stage NEN-pts, particularly as first-line treatment, since it is associated with statistically highly significant better outcome. NEC-G3 may benefit from surgery, but only in early stages and provided medical treatment is not required. 895 Endoscopic Mucosal Resection of Duodenal Carcinoid Tumors: A Single Tertiary Care Center Experience Ivan P. Harnden, Robert G. Walker, Bryan L. Balmadrid, Jorge V. Obando, Paul S. Jowell, Rebecca Burbridge Background: Duodenal carcinoid tumors are rare neoplasms, accounting for 3% of carcinoids in the gastrointestinal tract. The natural history of these tumors remains unclear. There is no consensus on the best treatment approach. Endoscopic mucosal resection (EMR) is felt to be appropriate for duodenal carcinoids less than 1cm in size confined to the mucosa and submucosa. In this retrospective study we examine the safety and efficacy of duodenal carcinoid EMR at a single tertiary care center. Methods: The endoscopy and pathology databases at Duke University Medical Center were reviewed for all patients with duodenal carcinoid tumors resected via EMR from 1999 to 2012. All patients had biopsy proven carcinoid tumors, and all had endoscopic ultrasound (EUS) prior to EMR to determine tumor depth. EMR was performed using submucosal injection followed by cap-ligation or standard snare polypectomy technique. The choice of technique was at the discretion of the endoscopist. Results: 43 duodenal carcinoids were resected in 40 patients. 17 patients were female (42.5%), 23 were male (57.5%). The mean age at time of resection was 64 (range 43 to 83). 39 tumors (91%) were located in the duodenal bulb, one (2%) at the junction of the first and second portions of the duodenum, and three (7%) in the second portion of the duodenum. One tumor was limited to the mucosa, while all others extended to the submucosa on EUS. Mean tumor size was 7.0mm (range 3.1-11.3mm) via EUS. 15 tumors (35%) were removed using standard snare technique and 28 (65%) using cap-ligation technique. All tumors were resected en-bloc. There were two perforations, both in patients undergoing cap-ligation EMR (4.7% of total EMR, 7.1% of cap-ligation EMR). One was managed endoscopically with clips and the other was managed surgically. Two patients (4.7%) had post-procedure GI bleeding requiring transfusion (one after snare polypectomy in the setting of anticoagulation and one after cap-ligation). 17 (40%) resected tumors had positive margins. 13 cases were lost to follow-up after the initial procedure (5 with positive margins, 8 with negative margins). Of the other 27 patients, three (11%) went on to surgical resection (all had positive margins). Mean follow-up time was 26.3 months. On follow-up EUS examinations, three patients had local recurrence (2/3 had positive margins on initial resection), and three patients had lymph node metastases (all had positive margins on initial resection). Conclusion: This is the largest single center study of its kind with 43 duodenal carcinoids resected from 40 patients. Endoscopic resection of duodenal carcinoids should be considered prior to surgical resection after EUS evaluation to exclude muscularis propria involvement. The significance of positive margins requires further study, and careful follow- up is necessary for patients with these tumors.
Transcript of 893 Assessing the Validity of Staging Classification for Small Intestinal Neuroendocrine Tumors
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sof NleH1 in WT EPEC (WT EPEC+pNleH1) increased survival at 12d to 94%. Protectionof wt loss was significantly better with NleH1 than 2 (Fig 1). Colon length was also improvedby EPEC expressing NleH1 (7.3±1.5 and 6.8±1.2 cm, WT+pNleH1 and ΔnleH1/2+pNleH1,resp; n=8) compared to ΔnleH1/2 (5.2±0.3 cm, n=4, p,0.05). H&E staining revealedsignificantly decreased colonic inflammation in animals infected with bacteria expressingNleH1 or NleH2 or both. In summary, these data show that NleH1 and 2 protect againstintestinal inflammation and rescue mice from DSS colitis with NleH1 being more effectivethan NleH2.
Figure 1: Protection from DSS-induced weight loss by NleH1 and 2.
893
Assessing the Validity of Staging Classification for Small IntestinalNeuroendocrine TumorsMichelle K. Kim, Richard R. Warner, Sasan Roayaie, Noam Harpaz, Stephen C. Ward,Steven H. Itzkowitz, Juan Wisnivesky
Introduction: Small intestinal neuroendocrine tumors (SI-NETs) are biologically heterogene-ous and have a variable clinical course. The neuroendocrine tumor societies have recentlyproposed a new TNM-based staging classification. In this study, we used data from a nationalpopulation-based cancer registry to validate the ability of this new staging system to predictpatient outcomes. Methods: We used the Surveillance, Epidemiology and End Results (SEER)database to identify all patients with confirmed SI-NETS diagnosed between 1988 and 2009.Information on primary tumor size, depth of tumor invasion, lymph node involvement, andpresence/absence of distant metastases was used to assign TNM stage. Kaplan Meier methodswere used to assess survival differences (up to 10 years from diagnosis) according to TNMstatus; Cox proportional hazards models were constructed to evaluate differences in prognosisafter controlling for potential confounders. Results: We identified 6,792 patients with patho-logically confirmed SI-NETs and complete stage information. The mean (standard deviation)patient age was 62.4±13.3 years, 52% were male, and 74% were white. Overall, 42% waslocated in the ileum, 23% in the duodenum, and 6% in the jejunum. According to currentstaging criteria, 11%, 26%, 49%, and 14% were stage I, II, III, and IV, respectively. KaplanMeier analysis showed increasingly worse survival with progressive higher T (T1 to T4)categories (p,0.0001). Similarly, patients with N0 (p,0.005) and M0 (p,0.0001) diseasehad improved survival as compared to N1 and M1 disease, respectively. However, survivalcurves stratified by stage showed overlap among several categories (Figure 1). Stage I andstage IIA cancer had comparable survival (10-year survival of 97% vs. 94%). Additionally,10 year survival for stage IIIB (79%) was better than for stage IIIA (72%). Stage IV cancerhad the worst outcomes (10-year survival of 44%). Adjusted analyses showed that T3 (hazardratio [HR]: 3.21, 95% confidence interval [CI]: 2.04-5.06) and T4 (HR: 5.33, 95% CI: 3.31-8.58) tumors had significantly worse survival than T1 tumors after adjusting for otherconfounders. T2 had comparable survival (HR 1.14, 95% CI: 0.70-1.85) to T1 tumors.However, N1 disease was not associated with worse survival in the adjusted model (HR:1.35, 95%CI: 0.86-2.10). Conclusions: While the newly proposed staging system for SI-NETs helps to predict prognosis in early and late stage disease, the classification does notdiscriminate well prognosis among patients with locoregional disease. Specifically, involve-ment of regional lymph nodes (N1 disease) does not appear to add independent prognosticinformation beyond that provided by T status. Further studies are needed to evaluate whetherthere are features of N1 disease that may further refine staging.
Figure 1. NET cancer-specific survival according to stage.
S-158AGA Abstracts
894
The Influence of Surgical Intervention on Long-Term Outcome ofGastroenteropancreatic Neuroendocrine Tumors (NET) in a Large GermanMulti Center Cohort StudyUlrich-Frank Pape, Nehara Begum, Andreas Pascher, Anja Rinke, Christine Wurst,Katharina Holzer, Marianne Pavel, Thomas J. Musholt, Peter E. Goretzki, Wolfram T.Knoefel, Detlef K. Bartsch
Neuroendocrine neoplasms (NEN) of the gastroenteropancreatic (GEP) system are a heteroge-neous group of malignant neplasms (including carcinoid tumors) with variable outcomeand a wide spectrum of treatment options. Due to variations in tumor biology, extent oftumor disease, symptomatology and treatment modalities prediction of outcome is complexand quite variable. Particularly the results of surgery are largely cohort- and center-depepdentand therefore the German NET-registry has collected and analyzed outcome results from alarge multi-centric German cohort with particular attention to influences of surgical interven-tion. Methods: 2358 patients (pts) with histologically proven NET diagnosed since 1999from 32 centres in Germany registered in the German NET registry were retrospectivelyanalyzed for pathological, clinical and treatment data and information on overall and NET-specific survival using Kaplan-Meier analysis and log-rank testing. Results: Primary tumorlocalizations were in pancreas (33%), small bowel (24%), stomach (7%), rectum (6%),appendix (4%), colon (2%), other localizations (11%) or of unknown primary tumor (13%)and 46% were already metastasized at initial diagnosis. During follow-up 16.1% of the ptsdied. Overall 2-, 5-, and 10- year survival rates (YSR) were 93, 82 and 66% while NET-specific 2-, 5-, and 10-YSR were 94, 85 and 70%. Survival was significantly better in patientswith early tumor disease (limited disease LD, stages I-IIIA) than in extensive disease (ED,stages IIIB and IV) in both NET-G1/" and NEC-G3 (p ,0.001 for LD vs. ED in bothsubgroups). 1559 surgical interventions were performed, 93.6% as first-line treatment and68.7% with curative intent. 5-YSR in operated pts (82%) was significantly better than innon-operated pts (61%, p,0.001) in the whole cohort as well as in pts operated withcurative (84%) vs. palliative (60%, p,0.001) intent. Besides WHO-classification resectionstatus appeared to be a statistically significant predictor of outcome with 5-YSR of 90% forR0, 82% for R1, 64% for Rx and 55% for R2-resection status after curatively intendedresection of the primary tumor. Similarly, long-term success of curatively intended resectionof metastases depended on R-status with 5-YSR of 90% for R0, 79% for R1, 66% forRx and 43% for R2-resections. Conclusion: Surgical resection of primary neuroendocrine(carcinoid) tumors as well as metastases with curative intent significantly improves long-term poutcome of GEP-NEN with the resection status indicating the long-term success ofsurgery. Surgery should therefore always be considered in early-stage NEN-pts, particularlyas first-line treatment, since it is associated with statistically highly significant better outcome.NEC-G3 may benefit from surgery, but only in early stages and provided medical treatmentis not required.
895
Endoscopic Mucosal Resection of Duodenal Carcinoid Tumors: A SingleTertiary Care Center ExperienceIvan P. Harnden, Robert G. Walker, Bryan L. Balmadrid, Jorge V. Obando, Paul S. Jowell,Rebecca Burbridge
Background: Duodenal carcinoid tumors are rare neoplasms, accounting for 3% of carcinoidsin the gastrointestinal tract. The natural history of these tumors remains unclear. There isno consensus on the best treatment approach. Endoscopic mucosal resection (EMR) is feltto be appropriate for duodenal carcinoids less than 1cm in size confined to the mucosa andsubmucosa. In this retrospective study we examine the safety and efficacy of duodenalcarcinoid EMR at a single tertiary care center. Methods: The endoscopy and pathologydatabases at Duke University Medical Center were reviewed for all patients with duodenalcarcinoid tumors resected via EMR from 1999 to 2012. All patients had biopsy provencarcinoid tumors, and all had endoscopic ultrasound (EUS) prior to EMR to determinetumor depth. EMR was performed using submucosal injection followed by cap-ligation orstandard snare polypectomy technique. The choice of technique was at the discretion of theendoscopist. Results: 43 duodenal carcinoids were resected in 40 patients. 17 patients werefemale (42.5%), 23 were male (57.5%). The mean age at time of resection was 64 (range43 to 83). 39 tumors (91%) were located in the duodenal bulb, one (2%) at the junctionof the first and second portions of the duodenum, and three (7%) in the second portion ofthe duodenum. One tumor was limited to the mucosa, while all others extended to thesubmucosa on EUS. Mean tumor size was 7.0mm (range 3.1-11.3mm) via EUS. 15 tumors(35%) were removed using standard snare technique and 28 (65%) using cap-ligationtechnique. All tumors were resected en-bloc. There were two perforations, both in patientsundergoing cap-ligation EMR (4.7% of total EMR, 7.1% of cap-ligation EMR). One wasmanaged endoscopically with clips and the other was managed surgically. Two patients(4.7%) had post-procedure GI bleeding requiring transfusion (one after snare polypectomyin the setting of anticoagulation and one after cap-ligation). 17 (40%) resected tumors hadpositive margins. 13 cases were lost to follow-up after the initial procedure (5 with positivemargins, 8 with negative margins). Of the other 27 patients, three (11%) went on to surgicalresection (all had positive margins). Mean follow-up time was 26.3 months. On follow-upEUS examinations, three patients had local recurrence (2/3 had positive margins on initialresection), and three patients had lymph node metastases (all had positive margins on initialresection). Conclusion: This is the largest single center study of its kind with 43 duodenalcarcinoids resected from 40 patients. Endoscopic resection of duodenal carcinoids shouldbe considered prior to surgical resection after EUS evaluation to exclude muscularis propriainvolvement. The significance of positive margins requires further study, and careful follow-up is necessary for patients with these tumors.
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