Background and Aims: There has been limited study of estrogen and progesterone receptor (ER/PR) expression in gastrointestinal neuroendocrine tumors (GINETs) despite emerging evidence of hormone receptor regulation of pancreatic islet cells. Beta cells express PR and progesterone has been implicated in the pathogenesis of gestational diabetes. There is conflicting information regarding HER2/neu protein overexpression in GINETs. Investigation of ER, PR and HER2/neu expression in GINETs is therefore warranted. Methods: A pathology database search identified 77 patients with primary pancreatic (40) or small intestinal (37) NETs diagnosed from 1991 to 2009. Ki67, ER, PR and HER2/neu were assessed via immunohistochemistry. ER and PR were interpreted as negative (0), 1+ (Allred score 3–7/8) or 2+ (Allred score 8/8), and HER2/neu was assessed according to ASCO/CAP guidelines for breast carcinoma. Clinical correlation and survival outcomes were ascertained by a retrospective clinical chart review. Results: 2+ PR staining was observed more often in pancreatic compared to small intestinal cases (55 vs. 8%; p < 0.001). All small intestinal NETs with 2+ PR were duodenal primaries. Cases with 2+ PR presented significantly less often with nodal or distant metastases compared to cases with 0/1+ PR (13 vs. 61.5%; p < 0.001) and had significantly improved disease-free survival (median 155 vs. 38 months; p = 0.037). Only one case demonstrated 2+ ER staining and all were negative for HER2/neu. Conclusion: GINETs with strong (2+) PR expression are associated with pancreatic/duodenal origin, lower stage disease, and more favorable clinical prognosis. Further study is needed to determine the clinical utility of PR expression in GINETs.

1.
Taal BG, Visser O: Epidemiology of neuroendocrine tumours. Neuroendocrinology 2004;80(suppl 1):3–7.
2.
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.
3.
Chetty R: An overview of practical issues in the diagnosis of gastroenteropancreatic neuroendocrine pathology. Arch Pathol Lab Med 2008;132:1285–1289.
4.
DeLellis RA, Lloyd RV, Heitz PU, Eng C: World Health Organization Classification of Tumours: Pathology and Genetics – Tumours of Endocrine Organs. Lyon, IARC Press, 2004.
5.
Kloppel G, Perren A, Heitz PU: The gastroenteropancreatic neuroendocrine cell system and its tumors: The WHO classification. Ann NY Acad Sci 2004;1014:13–27.
6.
Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Korner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B, all other Frascati Consensus Conference participants, European Neuroendocrine Tumor Society (ENETS): TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006;449:395–401.
7.
Rindi G, Kloppel G, Couvelard A, Komminoth P, Korner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B: TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007;451:757–762.
8.
Kloppel G, Couvelard A, Perren A, Komminoth P, McNicol AM, Nilsson O, Scarpa A, Scoazec JY, Wiedenmann B, Papotti M, Rindi G, Plockinger U, Mallorca Consensus Conference participants, European Neuroendocrine Tumor Society: ENETS consensus guidelines for the standards of care in neuroendocrine tumors: towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification. Neuroendocrinology 2009;90:162–166.
9.
Picard F, Wanatabe M, Schoonjans K, Lydon J, O’Malley BW, Auwerx J: Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta-cell proliferation. Proc Natl Acad Sci USA 2002;99:15644–15648.
10.
Sorenson RL, Brelje TC, Roth C: Effects of steroid and lactogenic hormones on islets of langerhans: A new hypothesis for the role of pregnancy steroids in the adaptation of islets to pregnancy. Endocrinology 1993;133:2227–2234.
11.
Viale G, Doglioni C, Gambacorta M, Zamboni G, Coggi G, Bordi C: Progesterone receptor immunoreactivity in pancreatic endocrine tumors – an immunocytochemical study of 156 neuroendocrine tumors of the pancreas, gastrointestinal and respiratory tracts, and skin. Cancer 1992;70:2268–2277.
12.
Pelosi G, Bresaola E, Bogina G, Pasini F, Rodella S, Castelli P, Iacono C, Serio G, Zamboni G: Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables. Hum Pathol 1996;27:1124–1134.
13.
Hammond ME, Hayes DF, Dowsett M, et al: American society of clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28:2784–2795.
14.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK, ToGA Trial Investigators: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687–697.
15.
Ruschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, Chenard MP, Penault-Llorca F, Nagelmeier I, Schlake W, Hofler H, Kreipe HH: HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch 2010;457:299–307.
16.
Okines AF, Cunningham D: Trastuzumab in gastric cancer. Eur J Cancer 2010;46:1949–1959.
17.
Evers BM, Rady PL, Tyring SK, Sanchez RL, Rajaraman S, Townsend CM Jr, Thompson JC: Amplification of the HER-2/neu protooncogene in human endocrine tumors. Surgery 1992;112:211–217, discussion 217–218.
18.
Wang DG, Johnston CF, Buchanan KD: Oncogene expression in gastroenteropancreatic neuroendocrine tumors: implications for pathogenesis. Cancer 1997;80:668–675.
19.
Goebel SU, Iwamoto M, Raffeld M, Gibril F, Hou W, Serrano J, Jensen RT: Her-2/neu expression and gene amplification in gastrinomas: correlations with tumor biology, growth, and aggressiveness. Cancer Res 2002;62:3702–3710.
20.
Yamaguchi M, Hirose K, Hirai N: HER2 expression in gastrointestinal carcinoid tumors: High in intestinal but not in gastric tumors. Surg Today 2007;37:270–271.
21.
Gilbert JA, Adhikari LJ, Lloyd RV, Rubin J, Haluska P, Carboni JM, Gottardis MM, Ames MM: Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors. Endocr Relat Cancer 2010;17:623–636.
22.
Lester SC, Bose S, Chen YY, Connolly JL, de Baca ME, Fitzgibbons PL, Hayes DF, Kleer C, O’Malley FP, Page DL, Smith BL, Tan LK, Weaver DL, Winer E, Members of the Cancer Committee, College of American Pathologists: Protocol for the examination of specimens from patients with invasive carcinoma of the breast. Arch Pathol Lab Med 2009;133:1515–1538.
23.
Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118–145.
24.
Moertel CG, Engstrom PF, Schutt AJ: Tamoxifen therapy for metastatic carcinoid tumor: A negative study. Ann Intern Med 1984;100:531–532.
25.
Lopez-Bonet E, Alonso-Ruano M, Barraza G, Vazquez-Martin A, Bernado L, Menendez JA: Solid neuroendocrine breast carcinomas: incidence, clinico-pathological features and immunohistochemical profiling. Oncol Rep 2008;20:1369–1374.
26.
Van Eeden S, Quaedvlieg PF, Taal BG, Offerhaus GJ, Lamers CB, Van Velthuysen ML: Classification of low-grade neuroendocrine tumors of midgut and unknown origin. Hum Pathol 2002;33:1126–1132.
27.
Proca DM, Frankel WL: Pancreatic endocrine tumors-c-erb B2 (her-2/neu), bcl-2, and p-53 immunohistochemical testing and their value in assessing prognosis. Appl Immunohistochem Mol Morphol 2008;16:44–47.
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.