Background/Aims: The prognostic value of histopathological grading and the growth pattern of small intestinal neuroendocrine tumors (SI-NET) is unclear. In particular, the cutoff level between grades G1 and G2 at Ki-67 index above 2% is an open issue, and both lower and higher cutoffs have been proposed. The morphological solid growth pattern (SGP) in SI-NET has been reported to be associated with worse survival. The present study investigates whether a Ki-67 index cutoff of 1% has a higher predictive power than one of 2% for disease-specific survival in SI-NET, and whether an SGP is associated with survival. Patients and Methods: From a population-based cohort, 127 SI-NET patients with available tumor specimens were included. Medical records and pathology reports were reviewed. Tumor specimens were reexamined to confirm the diagnosis, recalculate the Ki-67 index, and assess the presence of an SGP, introducing an SGP score from 0 to 3+. Results: The current grading system with a G1/G2 cutoff of 2% was more discriminative (HR 2.30; 95% CI 1.20-4.38, p = 0.012) than one with a lower cutoff of 1% (HR 1.65; 95% CI 0.95-2.87, p = 0.078) after adjustment for patient age and clinical stage. SGP score was strongly associated with clinical stage (p = 0.004) and histopathological grade (p < 0.001) but was not an independent prognostic factor for disease-specific survival in SI-NET (p = 0.122) after adjusting for age, stage, and grade. Conclusions: The present grading system of SI-NET is supported by our results. The SGP is not an independent prognostic factor for disease-specific survival in SI-NET.

Keywords:
Ileum, Jejunum, Solid growth pattern, Ki-67 index, Prognosis, Small intestine, Neuroendocrine tumor, Carcinoid
1.
Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, McNicol A-M, Nilsson O, Perren A, Scarpa A, Scoazec J-Y, Wiedenmann B: TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007;451:757−762.
2.
Sobin LH, Gospodarowicz MK, Wittekind C (eds): UICC International Union Against Cancer: TNM Classification of Malignant Tumours, ed 7. Chichester, Wiley-Blackwell, 2009.
3.
Klöppel G, Rindi G, Perren A, Komminoth P, Klimstra DS: The ENETS and AJCC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Arch 2010;456:595−597.
4.
Rindi G, Arnold R, Bosman FT, Capella C, Klimstra DS, Klöppel G, Komminoth P, Solcia E: Nomenclature and classification of neuroendocrine neoplasms of the digestive system; in Bosman FT, Carneiro F, Hruban RH, Theise ND (eds): WHO Classification of Tumours of the Digestive Tract, ed 4. Lyon, International Agency for Research on Cancer, 2010, pp 13−14.
5.
Capella C, Arnold R, Klimstra DS, Klöppel G, Komminoth P, Solcia E, Rindi G: Neuroendocrine neoplasms of the small intestine; in Bosman FT, Carneiro F, Hruban RH, Theise ND (eds): WHO Classification of Tumours of the Digestive Tract, ed 4. Lyon, International Agency for Research on Cancer, 2010, pp 102−107.
6.
Strosberg JR, Weber JM, Feldman M, Coppola D, Meredith K, Kvols LK: Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. J Clin Oncol 2013;31:420−425.
7.
Cunningham JL, Grimelius L, Sundin A, Agarwal S, Janson ET: Malignant ileocaecal serotonin-producing carcinoid tumours: the presence of a solid growth pattern and/or Ki67 index above 1% identifies patients with a poorer prognosis. Acta Oncol 2007;46:747−756.
8.
Soga J, Tazawa K: Pathologic analysis of carcinoids: histologic reevaluation of 62 cases. Cancer 1971;28:990−998.
9.
Jones RA, Dawson IM: Morphology and staining patterns of endocrine cell tumours in the gut, pancreas and bronchus and their possible significance. Histopathology 1977;1:137−150.
10.
Johnson LA, Lavin P, Moertel CG, Weiland L, Dayal Y, Doos WG, Geller SA, Cooper HS, Nime F, Massé S, Simson IW, Sumner H, Fölsch E, Engstrom P: Carcinoids: the association of histologic growth pattern and survival. Cancer 1983;51:882−889.
11.
Burke AP, Thomas RM, Elsayed AM, Sobin LH: Carcinoids of the jejunum and ileum: an immunohistochemical and clinicopathologic study of 167 cases. Cancer 1997;79:1086−1093.
12.
Landerholm K, Falkmer S, Järhult J: Epidemiology of small bowel carcinoids in a defined population. World J Surg 2010;34:1500−1505.
13.
Landerholm K, Zar N, Andersson RE, Falkmer SE, Järhult J: Survival and prognostic factors in patients with small bowel carcinoid tumour. Br J Surg 2011;98:1617−1624.
14.
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.
15.
Institute for Digital Research and Education - UCLA: Statistical computing seminars - survival analysis with Stata. http://www.ats.ucla.edu/STAT/stata/seminars/stata_survival/default.htm (accessed December 9, 2014).
16.
Newson RB: Comparing the predictive power of survival models using Harrell's c or Somers' D. Stata J 2010;10:339-358.
17.
Rindi G, Petrone G, Inzani F: The 2010 WHO classification of digestive neuroendocrine neoplasms: a critical appraisal four years after its introduction. Endocr Pathol 2014;25:186−192.
18.
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.
19.
Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler 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.
20.
Jann H, Roll S, Couvelard A, Hentic O, Pavel M, Müller-Nordhorn J, Koch M, Röcken C, Rindi G, Ruszniewski P, Wiedenmann B, Pape UF: Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. Cancer 2011;117:3332−3341.
21.
Norlén O, Stålberg P, Öberg K, Eriksson J, Hedberg J, Hessman O, Janson ET, Hellman P, Åkerström G: Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World J Surg 2012;36:1419−1431.
© 2015 S. Karger AG, Basel
2015
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.