Background: The natural history and the best modality of follow-up of atypical lung carcinoids (AC) remain ill defined. The aim of this study was to analyze recurrence-free survival (RFS) after complete resection (R0) of stage I-III pulmonary AC. Secondary objectives were prognostic parameters, the location of recurrences, and the modality of follow-up. Methods: A retrospective review of 540 charts of AC patients treated between 1998 and 2008 at 10 French and Italian centers with experience in lung neuroendocrine tumor management was undertaken. The exclusion criteria were MEN1-related tumor, history of another cancer, referral after tumor relapse, and being lost to follow-up. A central pathological review was performed in each country. Results: Sixty-two patients were included. After a median follow-up time of 91 months (mean 85, range 6-165), 35% of the patients experienced recurrence: 16% were regional recurrences and 19% were distant metastases. Median RFS was not reached. The 1-, 3-, and 5-year RFS rate was 90, 79, and 68%, respectively. In univariate analysis, lymph node involvement (p = 0.0001), stage (p = 0.0001), mitotic count (p = 0.004), and type of surgery (p = 0.043) were significantly associated with RFS. In multivariate analysis, lymph node involvement was significantly associated with RFS (HR 95% CI: 0.000-0.151; p = 0.004). During follow-up, somatostatin receptor scintigraphy, fibroscopy, and abdominal examination results were available for 22, 12, and 25 patients, respectively. The median time interval for imaging follow-up was 10 months. Conclusions: After complete resection of AC, recurrences were observed mostly within the first 5 years of follow-up, within bronchi, mediastinal nodes, the liver, and bones. In R0 patients, lymph node involvement could help to stratify follow-up intervals. Suboptimal imaging is evidenced.

Pearse AG: The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J Histochem Cytochem 1969;17:303-313.
Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG: WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, International Agency for Research on Cancer, 2015.
Sobin L, Gospodarowicz M, Wittekind C: TNM Classification of Malignant Tumours. New York, Wiley-Blackwell, 2010.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A: American Joint Committee on Cancer: AJCC Cancer Staging Manual, ed 7. New York, Springer, 2009.
Travis WD, Giroux DJ, Chansky K, Crowley J, Asamura H, Brambilla E, Jett J, Kennedy C, Rami-Porta R, Rusch VW, Goldstraw P; International Staging Committee and Participating Institutions: The IASLC Lung Cancer Staging Project: proposals for the inclusion of broncho-pulmonary carcinoid tumors in the forthcoming (seventh) edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2008;3:1213-1223.
Öberg K, Hellman P, Ferolla P, Papotti M; ESMO Guidelines Working Group: Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23(suppl 7):vii120-vii123.
Caplin ME, Baudin E, Ferolla P, Filosso P, García-Yuste M, Lim E, Öberg K, Pelosi G, Perren A, Rossi RE, Travis WD; ENETS Consensus Conference Participants: Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol 2015;26:1604-1620.
Surveillance, Epidemiology, and End Results (SEER) Program, November 2006 submission (1973-2004), SEER*Stat 6.3.5 program.
Filosso PL, Rena O, Donati G, Casadio C, Ruffini E, Papalia E, Oliaro A, Maggi G: Bronchial carcinoid tumors: surgical management and long-term outcome. J Thorac Cardiovasc Surg 2002;123:303-309.
Srirajaskanthan R, Toumpanakis C, Karpathakis A, Marelli L, Quigley AM, Dusmet M, Meyer T, Caplin ME: Surgical management and palliative treatment in bronchial neuroendocrine tumours: a clinical study of 45 patients. Lung Cancer 2009;65:68-73.
Ferguson MK, Landreneau RJ, Hazelrigg SR, Altorki NK, Naunheim KS, Zwischenberger JB, Kent M, Yim AP: Long-term outcome after resection for bronchial carcinoid tumors. Eur J Cardiothorac Surg 2000;18:156-161.
García-Yuste M, Matilla JM, Alvarez-Gago T, Duque JL, Heras F, Cerezal LJ, Ramos G: Prognostic factors in neuroendocrine lung tumors: a Spanish Multicenter Study. Spanish Multicenter Study of Neuroendocrine Tumors of the Lung of the Spanish Society of Pneumonology and Thoracic Surgery (EMETNE-SEPAR). Ann Thorac Surg 2000;70:258-263.
Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glazer M, Kramer MR: Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001;119:1647-1651.
Filosso PL, Ruffini E, Di Gangi S, Guerrera F, Bora G, Ciccone G, Galassi C, Solidoro P, Lyberis P, Oliaro A, Sandri A: Prognostic factors in neuroendocrine tumours of the lung: a single-centre experience. Eur J Cardiothorac Surg 2014;45:521-526; discussion 526.
Mezzetti M, Raveglia F, Panigalli T, Giuliani L, Lo Giudice F, Meda S, Conforti S: Assessment of outcomes in typical and atypical carcinoids according to latest WHO classification. Ann Thorac Surg 2003;76:1838-1842.
Cardillo G, Sera F, Di Martino M, Graziano P, Giunti R, Carbone L, Facciolo F, Martelli M: Bronchial carcinoid tumors: nodal status and long-term survival after resection. Ann Thorac Surg 2004;77:1781-1785.
Asamura H, Kameya T, Matsuno Y, Noguchi M, Tada H, Ishikawa Y, Yokose T, Jiang SX, Inoue T, Nakagawa K, Tajima K, Nagai K: Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol 2006;24:70-76.
Rea F, Rizzardi G, Zuin A, Marulli G, Nicotra S, Bulf R, Schiavon M, Sartori F: Outcome and surgical strategy in bronchial carcinoid tumors: single institution experience with 252 patients. Eur J Cardiothorac Surg 2007;31:186-191.
Ferolla P, Daddi N, Urbani M, Semeraro A, Ribacchi R, Giovenali P, Ascani S, De Angelis V, Crinò L, Puma F, Daddi G: Tumorlets, multicentric carcinoids, lymph-nodal metastases, and long-term behavior in bronchial carcinoids. J Thorac Oncol 2009;4:383-387.
Machuca TN, Cardoso PF, Camargo SM, Signori L, Andrade CF, Moreira AL, Moreira Jda S, Felicetti JC, Camargo JJ: Surgical treatment of bronchial carcinoid tumors: a single-center experience. Lung Cancer 2010;70:158-162.
Pusceddu S, Catena L, Valente M, Buzzoni R, Formisano B, Del Vecchio M, Ducceschi M, Tavecchio L, Fabbri A, Bajetta E: Long-term follow up of patients affected by pulmonary carcinoid at the Istituto Nazionale Tumori of Milan: a retrospective analysis. J Thorac Dis 2010;2:16-20.
Aydin E, Yazici U, Gulgosteren M, Agackiran Y, Kaya S, Gulhan E, Tastepe I, Karaoglanoglu N: Long-term outcomes and prognostic factors of patients with surgically treated pulmonary carcinoid: our institutional experience with 104 patients. Eur J Cardiothorac Surg 2011;39:549-554.
Daddi N, Schiavon M, Filosso PL, Cardillo G, Ambrogi MC, De Palma A, Luzzi L, Bandiera A, Casali C, Ruffato A, De Angelis V, Andriolo LG, Guerrera F, Carleo F, Davini F, Urbani M, Mattioli S, Morandi U, Zannini P, Gotti G, Loizzi M, Puma F, Mussi A, Ricci A, Oliaro A, Rea F: Prognostic factors in a multicentre study of 247 atypical pulmonary carcinoids. Eur J Cardiothorac Surg 2014;45:677-686.
Correia Sda S, Pinto C, Bernardo J: Pulmonary carcinoid: analysis of a single institutional experience and prognostic factors (in Portuguese). Acta Med Port 2014;27:749-754.
Filosso PL, Rena O, Guerrera F, Moreno Casado P, Sagan D, Raveglia F, Brunelli A, Welter S, Gust L, Pompili C, Casadio C, Bora G, Alvarez A, Zaluska W, Baisi A, Roesel C, Thomas PA: Clinical management of atypical carcinoid and large-cell neuroendocrine carcinoma: a multicentre study on behalf of the European Society of Thoracic Surgeons (ESTS) Neuroendocrine Tumours of the Lung Working Group. Eur J Cardiothorac Surg 2015;48:55-64.
Maurizi G, Ibrahim M, Andreetti C, D'Andrilli A, Ciccone AM, Pomes LM, Menna C, Pellegrini M, Venuta F, Rendina EA: Long-term results after resection of bronchial carcinoid tumour: evaluation of survival and prognostic factors. Interact Cardiovasc Thorac Surg 2014;19:239-244.
Stolz A, Harustiak T, Simonek J, Schutzner J, Polanecky O, Burkert J, Lischke R: Long-term outcomes and prognostic factors of patients with pulmonary carcinoid tumors. Neoplasma 2015;62:478-483.
Wittekind C, Compton CC, Greene FL, Sobin LH: TNM residual tumor classification revisited. Cancer 2002;94:2511-2516.
Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G, Barriuso J, Pavel M, O'Toole D, Walter T: Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 2015;22:657-664.
Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM, Krasinskas AM, Jang KT, Frankel WL, Balci S, Sigel C, Klimstra DS: The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol 2015;39:683-690.
Vélayoudom-Céphise FL, Duvillard P, Foucan L, Hadoux J, Chougnet CN, Leboulleux S, Malka D, Guigay J, Goere D, Debaere T, Caramella C, Schlumberger M, Planchard D, Elias D, Ducreux M, Scoazec JY, Baudin E: Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer 2013;20:649-657.
Milione M, Maisonneuve P, Spada F, Pellegrinelli A, Spaggiari P, Albarello L, Pisa E, Barberis M, Vanoli A, Buzzoni R, Pusceddu S, Concas L, Sessa F, Solcia E, Capella C, Fazio N, La Rosa S: The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology 2017;104:85-93.
Wahlberg J, Ekman B: Atypical or typical adrenocorticotropic hormone-producing pulmonary carcinoids and the usefulness of 11C-5-hydroxytryptophan positron emission tomography: two case reports. J Med Case Rep 2013;7:80.
Gustafsson BI, Kidd M, Chan AI, Malfertheiner MV, Modlin IM: Bronchopulmonary neuroendocrine tumors. Cancer 2008;113:5-21.
Faggiano A, Ferolla P, Grimaldi F, Campana D, Manzoni M, Davì MV, Bianchi A, Valcavi R, Papini E, Giuffrida D, Ferone D, Fanciulli G, Arnaldi G, Franchi GM, Francia G, Fasola G, Crinò L, Pontecorvi A, Tomassetti P, Colao A: Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study. J Endocrinol Invest 2012;35:817-823.
Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, Chen H, Jensen RT, Kim MK, Klimstra DS, Kulke MH, Liu EH, Metz DC, Phan AT, Sippel RS, Strosberg JR, Yao JC: Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 2013;42:557-577.
Righi L, Volante M, Tavaglione V, Billè A, Daniele L, Angusti T, Inzani F, Pelosi G, Rindi G, Papotti M: Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 “clinically aggressive” cases. Ann Oncol 2010;21:548-555.
Kaemmerer D, Specht E, Sänger J, Wirtz RM, Sayeg M, Schulz S, Lupp A: Somatostatin receptors in bronchopulmonary neuroendocrine neoplasms: new diagnostic, prognostic, and therapeutic markers. J Clin Endocrinol Metab 2015;100:831-840.
Lamarca A, Pritchard DM, Westwood T, Papaxoinis G, Nonaka D, Vinjamuri S, Valle JW, Manoharan P, Mansoor W: 68Gallium DOTANOC-PET imaging in lung carcinoids: impact on patients' management. Neuroendocrinology 2017, Epub ahead of print.
Kayani I, Conry BG, Groves AM, Win T, Dickson J, Caplin M, Bomanji JB: A comparison of 68Ga-DOTATATE and 18F-FDG PET/CT in pulmonary neuroendocrine tumors. J Nucl Med 2009;50:1927-1932.
Tsuta K, Raso MG, Kalhor N, Liu DD, Wistuba II, Moran CA: Histologic features of low- and intermediate-grade neuroendocrine carcinoma (typical and atypical carcinoid tumors) of the lung. Lung Cancer 2011;71:34-41.
Grimaldi F, Muser D, Beltrami CA, Machin P, Morelli A, Pizzolitto S, Talmassons G, Marciello F, Colao AA, Monaco R, Monaco G, Faggiano A: Partitioning of bronchopulmonary carcinoids in two different prognostic categories by Ki-67 score. Front Endocrinol (Lausanne) 2011;2:20.
Beasley MB, Thunnissen FB, Brambilla E, Hasleton P, Steele R, Hammar SP, Colby TV, Sheppard M, Shimosato Y, Koss MN, Falk R, Travis WD: Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000;31:1255-1265.
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.