Introduction: Pancreatic neuroendocrine neoplasms (PNENs) are uncommon neoplasms with a wide spectrum of clinical behavior. The objective of this study was to assess in a large cohort of patients the relative impact of prognostic factors on survival. Methods: From June 2001 through October 2010, 1,271 patients were prospectively registered online (www.getne.org) at the Spanish National Cancer Registry for Gastroenteropancreatic Neuroendocrine Tumors (RGETNE) by participating centers. Clinical and histopathological features were assessed as potential prognostic factors by uni- and multivariate analyses. Results: Of 483 PNENs, 171 (35%) were functional (F) and 312 (65%) non-functional (NF). NF-PNENs were associated with a higher incidence of histological features denoting more aggressive disease, such as poor tumor differentiation, Ki-67 >20%, or vascular invasion (NF- vs. F-PNENs, respectively, p < 0.05). Nevertheless, functionality was not a significant predictor of survival (p = 0.19). Stage at diagnosis, Ki-67 index, tumor differentiation and surgical resection of the primary tumor were all significant prognostic factors in univariate analysis. However, Ki-67 (>20 vs. ≤2%) (hazard ratio (HR) 2.21, p = 0.01) and surgical resection (yes vs. no) (HR 0.92, p = 0.001) were the only independent predictors of survival in multivariate analysis. Among patients who underwent surgery, high Ki-67 index (HR 10.37, p = 0.02) and poor differentiation (HR 8.16, p = 0.03) were the only independent predictors of clinical outcome. Conclusion: Ki-67 index and tumor differentiation are key prognostic factors influencing survival of patients with PNENs and, in contrast to what it is observed for other solid malignancies, they seem to have a greater impact on survival than the extent of disease. This should be borne in mind by physicians in order to appropriately tailor therapeutic strategies and surveillance of these patients.

Keywords:
Neuroendocrine tumors, Pancreatic, Ki-67, Prognosis, Registry, Survival
1.
Fischer L, Kleeff J, Esposito I, Hinz U, Zimmermann A, Friess H, Büchler MW: Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas. Br J Surg 2008;95:627-635.
2.
Plöckinger U, Rindi G, Arnold R, Eriksson B, Krenning EP, de Herder WW, Goede A, Caplin M, Oberg K, Reubi JC, Nilsson O, Delle Fave G, Ruszniewski P, Ahlman H, Wiedenmann B: Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 2004;80:394-424.
3.
Kulke MH, Anthony LB, Bushnell DL, de Herder WW, Goldsmith SJ, Klimstra DS, Marx SJ, Pasieka JL, Pommier RF, Yao JC, Jensen RT; North American Neuroendocrine Tumor Society (NANETS): NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas 2010;39:735-752.
4.
Kuiper P, Verspaget HW, van Slooten HJ, Overbeek L, Biemond I, Lamers CB: Pathological incidence of duodenopancreatic neuroendocrine tumors in the Netherlands: a Pathologisch Anatomisch Landelijk Geautomatiseerd Archief study. Pancreas 2010;39:1134-1139.
5.
Capella C, Heitz PU, Höfler H, Solcia E, Klöppel G: Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 1995;425:547-560.
6.
Solcia E, Klöppel G, Sobin LH: Histological Typing of Endocrine Tumours. World Health Organization International Histological Classification of Tumours, ed 2. Berlin, Springer, 2000.
7.
Hochwald SN, Zee S, Conlon KC, Colleoni R, Louie O, Brennan MF, Klimstra DS: Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 2002;20:2633-2642.
8.
Bilimoria KY, Talamonti MS, Tomlinson JS, Stewart AK, Winchester DP, Ko CY, Bentrem DJ: Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3,851 patients. Ann Surg 2008;247:490-500.
9.
Ballian N, Loeffler AG, Rajamanickam V, Norstedt PA, Weber SM, Cho CS: A simplified prognostic system for resected pancreatic neuroendocrine neoplasms. HPB 2009;11:422-428.
10.
Klöppel G, Perren A, Heitz PU: The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann NY Acad Sci 2004;1014:13-27.
11.
Rindi G, Kloppel G, Ahlmann H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B: TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006;449:395-401.
12.
Sobin LH, Gospodarowicz MK, Wittekind C: UICC: TNM Classification of Malignant Tumours, ed 7. Oxford, Wiley-Blackwell, 2009.
13.
Bosman FT, Carneiro F, Hruban RH, et al: WHO Classification of Tumours of the Digestive System, ed 4. Lyon, France, IARC Press, 2010.
14.
Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, Díaz-Pérez JA, Martínez Del Prado MP, Alonso Orduña V, Sevilla-García I, Villabona-Artero C, Beguiristain-Gómez A, Llanos-Muñoz M, Marazuela M, Alvarez-Escola C, Castellano D, Vilar E, Jiménez-Fonseca P, Teulé A, Sastre-Valera J, Benavent-Viñuelas M, Monleon A, Salazar R: Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol 2010;21:1794-1803.
15.
Kaplan E, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481.
16.
La Rosa S, Sessa F, Capella C, Riva C, Leone BE, Klersy C, Rindi G, Solcia E: Prognostic criteria in nonfunctioning pancreatic endocrine tumors. Virchows Arch 1996;429:323-333.
17.
Panzuto F, Nasoni S, Falconi M, Corleto VD, Capurso G, Cassetta S, Di Fonzo M, Tornatore V, Milione M, Angeletti S, Cattaruzza MS, Ziparo V, Bordi C, Pederzoli P, Delle Fave G: Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 2005;12:1083-1092.
18.
Gullo L, Migliori M, Falconi M, Pederzoli P, Bettini R, Casadei R, Delle Fave G, Corleto VD, Ceccarelli C, Santini D, Tomassetti P: Nonfunctioning pancreatic endocrine tumors: a multicenter clinical study. Am J Gastroenterol 2003;98:2435-2439.
19.
Wang SE, Su CH, Kuo YJ, Shyr YM, Li AF, Chen TH, Wu CW, Lee CH: Comparison of functional and nonfunctional neuroendocrine tumors in the pancreas and peripancreatic region. Pancreas 2011;40:253-259.
20.
Bilimoria KY, Tomlinson JS, Merkow RP, Stewart AK, Ko CY, Talamonti MS, Bentrem DJ: Clinicopathologic features and treatment trends of pancreatic neuroendocrine tumors: analysis of 9,821 patients. J Gastrointest Surg 2007;11:1460-1467.
21.
Kazanjian KK, Reber HA, Hines OJ: Resection of pancreatic neuroendocrine tumors: results of 70 cases. Arch Surg 2006;141:765-769.
22.
Schurr PG, Strate T, Rese K, Kaifi JT, Reichelt U, Petri S, Kleinhans H, Yekebas EF, Izbicki JR: Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience. Ann Surg 2007;245:273-281.
23.
Sarmiento JM, Farnell MB, Que FG, Nagorney DM: Pancreaticoduodenectomy for islet cell tumors of the head of the pancreas: long-term survival analysis. World J Surg 2002;26:1267-1271.
24.
Solorzano CC, Lee JE, Pisters PW, Vauthey JN, Ayers GD, Jean ME, Gagel RF, Ajani JA, Wolff RA, Evans DB: Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients. Surgery 2001;130:1078-1085.
25.
Tomassetti P, Campana D, Piscitelli L, Casadei R, Santini D, Nori F, Morselli-Labate AM, Pezzilli R, Corinaldesi R: Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol 2005;16:1806-1810.
26.
Chung JC, Choi DW, Jo SH, Heo JS, Choi SH, Kim YI: Malignant nonfunctioning endocrine tumors of the pancreas: predictive factors for survival after surgical treatment. World J Surg 2007;31:579-785.
27.
Sakka N, Smith RA, Whelan P, Ghaneh P, Sutton R, Raraty M, Campbell F, Neoptolemos JP: A preoperative prognostic score for resected pancreatic and periampullary neuroendocrine tumours. Pancreatology 2009;9:670-676.
28.
Bettini R, Boninsegna L, Mantovani W, Capelli P, Bassi C, Pederzoli P, Delle Fave GF, Panzuto F, Scarpa A, Falconi M: Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours. Ann Oncol 2008;19:903-908.
29.
Bahra M, Jacob D, Pascher A, Plockinger U, Kristiansen G, Neuhaus P, Langrehr JM: Surgical strategies and predictors of outcome for malignant neuroendocrine tumors of the pancreas. J Gastroenterol Hepatol 2007;22:930-935.
30.
Martin RC, Kooby DA, Weber SM, Merchant NB, Parikh AA, Cho CS, Ahmad SA, Kim HJ, Hawkins W, Scoggins CR: Analysis of 6,747 pancreatic neuroendocrine tumors for a proposed staging system. J Gastrointest Surg 2011;15:175-183.
31.
Bettini R, Partelli S, Boninsegna L, Capelli P, Crippa S, Pederzoli P, Scarpa A, Falconi M: Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 2011;150:75-82.
32.
Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B: Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res 2008;14:7798-7803.
33.
Chu QD, Hill HC, Douglass HO, Driscoll D, Smith JL, Nava HR, Gibbs JF: Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas. Ann Surg Oncol 2002;9:855-862.
34.
Kent RB, van Heerden JA, Wheiland LH: Nonfunctioning islet cell tumors. Ann Surg 1981;193:185-190.
35.
Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM: The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011;40:1-18.
36.
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB: One hundred years after ‘carcinoid': epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-3072.
37.
Pape UF, Jann H, Müller-Nordhorn J, Bockelbrink A, Berndt U, Willich SN, Koch M, Röcken C, Rindi G, Wiedenmann B: Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 2008;113:256-265.
38.
Fendrich V, Langer P, Celik I, Bartsch DK, Zielke A, Ramaswamy A, Rothmund M: An aggressive surgical approach leads to long-term survival in patients with pancreatic endocrine tumors. Ann Surg 2006;244:845-853.
39.
Hill JS, McPhee JT, McDade TP, Zhou Z, Sullivan ME, Whalen GF, Tseng JF: Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer 2009;15:741-751.
40.
Nguyen SQ, Angel LP, Divino CM, Schluender S, Warner RR: Surgery in malignant pancreatic neuroendocrine tumours. J Surg Oncol 2007;96:397-403.
41.
Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R, Panzuto F, Pederzoli P, delle Fave G, Falconi M: Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 2010;23:824-833.
42.
Panzuto F, Boninsegna L, Fazio N, Campana D, Pia Brizzi M, Capurso G, Scarpa A, De Braud F, Dogliotti L, Tomassetti P, Delle Fave G, Falconi M: Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol 2011;29:2372-2377.
43.
Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Büchler MW, Capella C, Caplin M, Couvelard A, Doglioni C, Delle Fave G, Fischer L, Fusai G, de Herder WW, Jann H, Komminoth P, de Krijger RR, La Rosa S, Luong TV, Pape U, Perren A, Ruszniewski P, Scarpa A, Schmitt A, Solcia E, Wiedenmann B: TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 2012;104:764-777.
44.
Sellner F, Thalhammer S, Stättner S, Karner J, Klimpfinger M: TNM stage and grade in predicting the prognosis of operated, non-functioning neuroendocrine carcinoma of the pancreas - a single-institution experience. J Surg Oncol 2011;104:17-21.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.