Molecular Diagnosis & Therapy

, Volume 22, Issue 2, pp 169–177 | Cite as

Neuroendocrine Pulmonary Tumors of Low, Intermediate and High Grade: Anatomopathological Diagnosis—Prognostic and Predictive Factors

  • José Manuel Cameselle-Teijeiro
  • José Antonio Mato Mato
  • Ovidio Fernández Calvo
  • Jesús García Mata
Review Article


Neuroendocrine tumors (NETs) belong to a heterogeneous family of rare tumors with very broad and complex clinical behavior. Due to their heterogeneity, the lack of specific symptoms and the absence of sensitive methods for early detection, patients are usually diagnosed when the disease is in an advanced state for which curative treatments are scarce. In most cases, these few treatments try to prolong the survival of patients, maintaining the quality of life. The identification of biomarkers could help to improve early diagnosis and to choose the most suitable therapeutic strategy. This paper provides a review of the current histopathological diagnostic approaches for lung NET subtypes, including the predictive and prognostic factors, to help in the early diagnosis of this disease.



The authors wish to thank Dr. Fernando Sánchez Barbero and Springer Healthcare from Springer Nature group for help in the preparation of the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors (JMC-T, JAMM, OFC and JGM) declare that they do not have any conflict of interest that may inappropriately influence this work.


Novartis provided financial support for medical writing services. José Manuel Cameselle-Teijeiro was also partially supported by Grant PI15/01501/co-financed-FEDER from the Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Spain.


  1. 1.
    Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9(1):61–72.CrossRefPubMedGoogle Scholar
  2. 2.
    Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134(11):1628–38.PubMedGoogle Scholar
  3. 3.
    Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer. 2015;121(4):589–97.CrossRefPubMedGoogle Scholar
  4. 4.
    Klimstra DS, Modlin IR, Adsay NV, Chetty R, Deshpande V, Gonen M, Jensen RT, Kidd M, Kulke MH, Lloyd RV, Moran C, Moss SF, Oberg K, O’Toole D, Rindi G, Robert ME, Suster S, Tang LH, Tzen CY, Washington MK, Wiedenmann B, Yao J. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol. 2010;34(3):300–13.CrossRefPubMedGoogle Scholar
  5. 5.
    Matias-Guiu X, Barriuso J, Aranda I, Capdevila J, Cuatrecasas M, Gonzalez E, Gonzalez-Campora R, Jimenez-Fonseca P, Vilardell F, Garcia-Carbonero R. Guidelines for biomarker testing in gastroenteropancreatic endocrine tumours. A national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology. Rev Esp Patol. 2013;46(4):222–36.Google Scholar
  6. 6.
    Travis WD, Brambilla C, Burke AP, Marx A, Nicholson AG. WHO classification of tumours of lung, pleura, thymus and heart. 4th ed. Lyon: IARC; 2015.Google Scholar
  7. 7.
    Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR, editors. AJCC cancer staging manual. 8th ed. Chicago, Illinois: Springer; 2017.Google Scholar
  8. 8.
    Reid MD, Bagci P, Ohike N, Saka B, Erbarut Seven I, Dursun N, Balci S, Gucer H, Jang KT, Tajiri T, Basturk O, Kong SY, Goodman M, Akkas G, Adsay V. Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies. Mod Pathol. 2015;28(5):686–94.CrossRefPubMedGoogle Scholar
  9. 9.
    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(5):683–90.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Rindi G, Bordi C, La Rosa S, Solcia E, Delle G. Fave, Gruppo Italiano Patologi Apparato Digerente (GIPAD), Societa Italiana di Anatomia Patologica e Citopatologia Diagnostica/International Academy of Pathology Italian division (SIAOEC/IAP), Gastroenteropancreatic (neuro) endocrine neoplasms: the histology report. Dig Liver Dis. 2011;43(Suppl 4):S356–60.CrossRefPubMedGoogle Scholar
  11. 11.
    Travis WD, Rush W, Flieder DB, Falk R, Fleming MV, Gal AA, Koss MN. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol. 1998;22(8):934–44.CrossRefPubMedGoogle Scholar
  12. 12.
    Pelosi G, Rodriguez J, Viale G, Rosai J. Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients. Am J Surg Pathol. 2005;29(2):179–87.CrossRefPubMedGoogle Scholar
  13. 13.
    Pelosi G, Rindi G, Travis WD, Papotti M. Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol. 2014;9(3):273–84.CrossRefPubMedGoogle Scholar
  14. 14.
    Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumors of the digestive system. Lyon: IARC; 2000.Google Scholar
  15. 15.
    Solcia E, Kloeppel G, Sobin LH. Histological typing of endocrine tumours. Berlin: Springer; 2000.CrossRefGoogle Scholar
  16. 16.
    Chan ES, Alexander J, Swanson PE, Jain D, Yeh MM. PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrine neoplasms. Am J Surg Pathol. 2012;36(5):737–43.CrossRefPubMedGoogle Scholar
  17. 17.
    Detterbeck FC. Clinical presentation and evaluation of neuroendocrine tumors of the lung. Thorac Surg Clin. 2014;24(3):267–76.CrossRefPubMedGoogle Scholar
  18. 18.
    Elamin MB, Murad MH, Mullan R, Erickson D, Harris K, Nadeem S, Ennis R, Erwin PJ, Montori VM. Accuracy of diagnostic tests for Cushing’s syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab. 2008;93(5):1553–62.CrossRefPubMedGoogle Scholar
  19. 19.
    Findling JW, Raff H, Aron DC. The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2004;89(3):1222–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Yaneva M, Mosnier-Pudar H, Dugue MA, Grabar S, Fulla Y, Bertagna X. Midnight salivary cortisol for the initial diagnosis of Cushing’s syndrome of various causes. J Clin Endocrinol Metab. 2004;89(7):3345–51.CrossRefPubMedGoogle Scholar
  21. 21.
    Oberg 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):vii120–3.PubMedGoogle Scholar
  22. 22.
    Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, Oberg 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(8):1604–20.CrossRefPubMedGoogle Scholar
  23. 23.
    Jeung MY, Gasser B, Gangi A, Charneau D, Ducroq X, Kessler R, Quoix E, Roy C. Bronchial carcinoid tumors of the thorax: spectrum of radiologic findings. Radiographics. 2002;22(2):351–65.CrossRefPubMedGoogle Scholar
  24. 24.
    Kramer H, Groen HJ. Current concepts in the mediastinal lymph node staging of nonsmall cell lung cancer. Ann Surg. 2003;238(2):180–8.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Ameri P, Gatto F, Arvigo M, Villa G, Resmini E, Minuto F, Murialdo G, Ferone D. Somatostatin receptor scintigraphy in thoracic diseases. J Endocrinol Investig. 2007;30(10):889–902.CrossRefGoogle Scholar
  26. 26.
    Van Binnebeek S, Vanbilloen B, Baete K, Terwinghe C, Koole M, Mottaghy FM, Clement PM, Mortelmans L, Bogaerts K, Haustermans K, Nackaerts K, Van Cutsem E, Verslype C, Verbruggen A, Deroose CM. Comparison of diagnostic accuracy of (111)In-pentetreotide SPECT and (68)Ga-DOTATOC PET/CT: a lesion-by-lesion analysis in patients with metastatic neuroendocrine tumours. Eur Radiol. 2016;26(3):900–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Baum RP, Prasad V, Hommann M, Horsch D. Receptor PET/CT imaging of neuroendocrine tumors. Recent Results Cancer Res. 2008;170:225–42.CrossRefPubMedGoogle Scholar
  28. 28.
    Binderup T, Knigge U, Loft A, Federspiel B, Kjaer A. 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clin Cancer Res. 2010;16(3):978–85.CrossRefPubMedGoogle Scholar
  29. 29.
    Aguayo SM, Miller YE, Waldron JA Jr, Bogin RM, Sunday ME, Staton GW Jr, Beam WR, King TE Jr. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med. 1992;327(18):1285–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Marchevsky AM, Walts AE. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Semin Diagn Pathol. 2015;32(6):438–44.CrossRefPubMedGoogle Scholar
  31. 31.
    Escudero AG, Zarco ER, Arjona JC, Moreno MJ, Rodriguez KG, Benitez AV, Campora RG. Expression of developing neural transcription factors in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Virchows Arch. 2016;469(3):357–63.CrossRefPubMedGoogle Scholar
  32. 32.
    Rizvi SM, Goodwill J, Lim E, Yap YK, Wells AU, Hansell DM, Davis P, Selim AG, Goldstraw P, Nicholson AG. The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and non-neuroendocrine cell carcinomas. Histopathology. 2009;55(3):332–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Marchevsky AM, Wirtschafter E, Walts AE. The spectrum of changes in adults with multifocal pulmonary neuroendocrine proliferations: what is the minimum set of pathologic criteria to diagnose DIPNECH? Hum Pathol. 2015;46(2):176–81.CrossRefPubMedGoogle Scholar
  34. 34.
    Rossi G, Cavazza A, Spagnolo P, Sverzellati N, Longo L, Jukna A, Montanari G, Carbonelli C, Vincenzi G, Bogina G, Franco R, Tiseo M, Cottin V, Colby TV. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome. Eur Respir J. 2016;47(6):1829–41.CrossRefPubMedGoogle Scholar
  35. 35.
    Carr LL, Kern JA, Deutsch GH. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and neuroendocrine hyperplasia of infancy. Clin Chest Med. 2016;37(3):579–87.CrossRefPubMedGoogle Scholar
  36. 36.
    Valli M, Fabris GA, Dewar A, Hornall D, Sheppard MN. Atypical carcinoid tumour of the lung: a study of 33 cases with prognostic features. Histopathology. 1994;24(4):363–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Travis WD. Advances in neuroendocrine lung tumors. Ann Oncol. 2010;21(Suppl 7):vii65–71.CrossRefPubMedGoogle Scholar
  38. 38.
    Quinn AM, Chaturvedi A, Nonaka D. High-grade neuroendocrine carcinoma of the lung with carcinoid morphology: a study of 12 cases. Am J Surg Pathol. 2017;41(2):263–70.CrossRefPubMedGoogle Scholar
  39. 39.
    Lantuejoul S, Moro D, Michalides RJ, Brambilla C, Brambilla E. Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors. Am J Surg Pathol. 1998;22(10):1267–76.CrossRefPubMedGoogle Scholar
  40. 40.
    Min KW. Two different types of carcinoid tumors of the lung: immunohistochemical and ultrastructural investigation and their histogenetic consideration. Ultrastruct Pathol. 2013;37(1):23–35.CrossRefPubMedGoogle Scholar
  41. 41.
    Sturm N, Rossi G, Lantuejoul S, Laverriere MH, Papotti M, Brichon PY, Brambilla C, Brambilla E. 34BetaE12 expression along the whole spectrum of neuroendocrine proliferations of the lung, from neuroendocrine cell hyperplasia to small cell carcinoma. Histopathology. 2003;42(2):156–66.CrossRefPubMedGoogle Scholar
  42. 42.
    Nonaka D, Papaxoinis G, Mansoor W. Diagnostic utility of orthopedia homeobox (OTP) in pulmonary carcinoid tumors. Am J Surg Pathol. 2016;40(6):738–44.CrossRefPubMedGoogle Scholar
  43. 43.
    Sturm N, Rossi G, Lantuejoul S, Papotti M, Frachon S, Claraz C, Brichon PY, Brambilla C, Brambilla E. Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids. Hum Pathol. 2002;33(2):175–82.CrossRefPubMedGoogle Scholar
  44. 44.
    Du EZ, Goldstraw P, Zacharias J, Tiffet O, Craig PJ, Nicholson AG, Weidner N, Yi ES. TTF-1 expression is specific for lung primary in typical and atypical carcinoids: TTF-1-positive carcinoids are predominantly in peripheral location. Hum Pathol. 2004;35(7):825–31.CrossRefPubMedGoogle Scholar
  45. 45.
    Saqi A, Alexis D, Remotti F, Bhagat G. Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. Am J Clin Pathol. 2005;123(3):394–404.CrossRefPubMedGoogle Scholar
  46. 46.
    La Rosa S, Chiaravalli AM, Placidi C, Papanikolaou N, Cerati M, Capella C. TTF1 expression in normal lung neuroendocrine cells and related tumors: immunohistochemical study comparing two different monoclonal antibodies. Virchows Arch. 2010;457(4):497–507.CrossRefPubMedGoogle Scholar
  47. 47.
    Sica G, Wagner PL, Altorki N, Port J, Lee PC, Vazquez MF, Saqi A. Immunohistochemical expression of estrogen and progesterone receptors in primary pulmonary neuroendocrine tumors. Arch Pathol Lab Med. 2008;132(12):1889–95.PubMedGoogle Scholar
  48. 48.
    Bonato M, Cerati M, Pagani A, Papotti M, Bosi F, Bussolati G, Capella C. Differential diagnostic patterns of lung neuroendocrine tumours. A clinico-pathological and immunohistochemical study of 122 cases. Virchows Arch A Pathol Anat Histopathol. 1992;420(3):201–11.CrossRefPubMedGoogle Scholar
  49. 49.
    Ejaz S, Vassilopoulou-Sellin R, Busaidy NL, Hu MI, Waguespack SG, Jimenez C, Ying AK, Cabanillas M, Abbara M, Habra MA. Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience. Cancer. 2011;117(19):4381–9.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Boddaert G, Grand B, Le Pimpec-Barthes F, Cazes A, Bertagna X, Riquet M. Bronchial carcinoid tumors causing Cushing’s syndrome: more aggressive behavior and the need for early diagnosis. Ann Thorac Surg. 2012;94(6):1823–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Nicholson SA, Beasley MB, Brambilla E, Hasleton PS, Colby TV, Sheppard MN, Falk R, Travis WD. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol. 2002;26(9):1184–97.CrossRefPubMedGoogle Scholar
  52. 52.
    Hiroshima K, Iyoda A, Shida T, Shibuya K, Iizasa T, Kishi H, Tanizawa T, Fujisawa T, Nakatani Y. Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis. Mod Pathol. 2006;19(10):1358–68.CrossRefPubMedGoogle Scholar
  53. 53.
    Wick MR. Immunohistology of neuroendocrine and neuroectodermal tumors. Semin Diagn Pathol. 2000;17(3):194–203.PubMedGoogle Scholar
  54. 54.
    Masai K, Tsuta K, Kawago M, Tatsumori T, Kinno T, Taniyama T, Yoshida A, Asamura H, Tsuda H. Expression of squamous cell carcinoma markers and adenocarcinoma markers in primary pulmonary neuroendocrine carcinomas. Appl Immunohistochem Mol Morphol. 2013;21(4):292–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Kaufmann O, Dietel M. Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites. Histopathology. 2000;36(5):415–20.CrossRefPubMedGoogle Scholar
  56. 56.
    Brown AF, Sirohi D, Fukuoka J, Cagle PT, Policarpio-Nicolas M, Tacha D, Jagirdar J. Tissue-preserving antibody cocktails to differentiate primary squamous cell carcinoma, adenocarcinoma, and small cell carcinoma of lung. Arch Pathol Lab Med. 2013;137(9):1274–81.CrossRefPubMedGoogle Scholar
  57. 57.
    Camps C, Sirera R, Bremnes RM, Garde J, Safont MJ, Blasco A, Berrocal A, Sanchez JJ, Calabuig C, Martorell M. Analysis of c-kit expression in small cell lung cancer: prevalence and prognostic implications. Lung Cancer. 2006;52(3):343–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Lopez-Martin A, Ballestin C, Garcia-Carbonero R, Castano A, Lopez-Rios F, Lopez-Encuentra A, Sanchez-Cespedes M, Castellano D, Bartolome A, Cortes-Funes H, Paz-Ares L. Prognostic value of KIT expression in small cell lung cancer. Lung Cancer. 2007;56(3):405–13.CrossRefPubMedGoogle Scholar
  59. 59.
    Dy GK, Miller AA, Mandrekar SJ, Aubry MC, Langdon RM Jr, Morton RF, Schild SE, Jett JR, Adjei AA. A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study. Ann Oncol. 2005;16(11):1811–6.CrossRefPubMedGoogle Scholar
  60. 60.
    Yang F, Gao Y, Geng J, Qu D, Han Q, Qi J, Chen G. Elevated expression of SOX2 and FGFR1 in correlation with poor prognosis in patients with small cell lung cancer. Int J Clin Exp Pathol. 2013;6(12):2846–54.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Cardnell RJ, Li L, Sen T, Bara R, Tong P, Fujimoto J, Ireland AS, Guthrie MR, Bheddah S, Banerjee U, Kalu NN, Fan YH, Dylla SJ, Johnson FM, Wistuba II, Oliver TG, Heymach JV, Glisson BS, Wang J, Byers L-A. Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies. Oncotarget. 2017;8(43):73419–32.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yeh YC, Chou TY. Pulmonary neuroendocrine tumors: study of 90 cases focusing on clinicopathological characteristics, immunophenotype, preoperative biopsy, and frozen section diagnoses. J Surg Oncol. 2014;109(3):280–6.CrossRefPubMedGoogle Scholar
  63. 63.
    Rossi G, Mengoli MC, Cavazza A, Nicoli D, Barbareschi M, Cantaloni C, Papotti M, Tironi A, Graziano P, Paci M, Stefani A, Migaldi M, Sartori G, Pelosi G. Large cell carcinoma of the lung: clinically oriented classification integrating immunohistochemistry and molecular biology. Virchows Arch. 2014;464(1):61–8.CrossRefPubMedGoogle Scholar
  64. 64.
    Iyoda A, Travis WD, Sarkaria IS, Jiang SX, Amano H, Sato Y, Saegusa M, Rusch VW, Satoh Y. Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma. Exp Ther Med. 2011;2(6):1041–5.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Pelosi G, Rossi G, Cavazza A, Righi L, Maisonneuve P, Barbareschi M, Graziano P, Pastorino U, Garassino M, de Braud F, Papotti M. DeltaNp63 (p40) distribution inside lung cancer: a driver biomarker approach to tumor characterization. Int J Surg Pathol. 2013;21(3):229–39.CrossRefPubMedGoogle Scholar
  66. 66.
    Pelosi G, Pasini F, Olsen Stenholm C, Pastorino U, Maisonneuve P, Sonzogni A, Maffini F, Pruneri G, Fraggetta F, Cavallon A, Roz E, Iannucci A, Bresaola E, Viale G. p63 immunoreactivity in lung cancer: yet another player in the development of squamous cell carcinomas? J Pathol. 2002;198(1):100–9.CrossRefPubMedGoogle Scholar
  67. 67.
    Matsumura Y, Umemura S, Ishii G, Tsuta K, Matsumoto S, Aokage K, Hishida T, Yoshida J, Ohe Y, Suzuki H, Ochiai A, Goto K, Nagai K, Tsuchihara K. Expression profiling of receptor tyrosine kinases in high-grade neuroendocrine carcinoma of the lung: a comparative analysis with adenocarcinoma and squamous cell carcinoma. J Cancer Res Clin Oncol. 2015;141(12):2159–70.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Makino T, Mikami T, Hata Y, Otsuka H, Koezuka S, Isobe K, Tochigi N, Shibuya K, Homma S, Iyoda A. Comprehensive biomarkers for personalized treatment in pulmonary large cell neuroendocrine carcinoma: a comparative analysis with adenocarcinoma. Ann Thorac Surg. 2016;102(5):1694–701.CrossRefPubMedGoogle Scholar
  69. 69.
    Derks J, Leblay N, Thunnissen E, van Suylen RJ, den Bakker M, Groen HJ, Smit EF, Damhuis R, van den Broek EC, Chabrier A, Foll M, McKay JD, Fernandez-Cuesta L, Speel EM, Dingemans AC. Molecular subtypes of pulmonary large cell neuroendocrine carcinoma predict chemotherapy treatment outcome. Clin Cancer Res. 2017. (Epub ahead of print).PubMedGoogle Scholar
  70. 70.
    Cao C, Yan TD, Kennedy C, Hendel N, Bannon PG, McCaughan BC. Bronchopulmonary carcinoid tumors: long-term outcomes after resection. Ann Thorac Surg. 2011;91(2):339–43.CrossRefPubMedGoogle Scholar
  71. 71.
    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, Multi-Institutional Italian Pathology Group. Prognostic factors in a multicentre study of 247 atypical pulmonary carcinoids. Eur J Cardiothorac Surg. 2014;45(4):677–86.CrossRefPubMedGoogle Scholar
  72. 72.
    McCloskey P, Balduyck B, Van Schil PE, Faivre-Finn C, O’Brien M. Radical treatment of non-small cell lung cancer during the last 5 years. Eur J Cancer. 2013;49(7):1555–64.CrossRefPubMedGoogle Scholar
  73. 73.
    Jhun BW, Lee KJ, Jeon K, Suh GY, Chung MP, Kim H, Kwon OJ, Sun JM, Ahn JS, Ahn MJ, Park K, Choi JY, Lee KS, Han J, Um SW. Clinical applicability of staging small cell lung cancer according to the seventh edition of the TNM staging system. Lung Cancer. 2013;81(1):65–70.CrossRefPubMedGoogle Scholar
  74. 74.
    Gaspar LE, McNamara EJ, Gay EG, Putnam JB, Crawford J, Herbst RS, Bonner JA. Small-cell lung cancer: prognostic factors and changing treatment over 15 years. Clin Lung Cancer. 2012;13(2):115–22.CrossRefPubMedGoogle Scholar
  75. 75.
    Svensson G, Ewers SB, Ohlsson O, Olsson H. Prognostic factors in lung cancer in a defined geographical area over two decades with a special emphasis on gender. Clin Respir J. 2013;7(1):91–100.CrossRefPubMedGoogle Scholar
  76. 76.
    Videtic GM, Truong PT, Ash RB, Yu EW, Kocha WI, Vincent MD, Tomiak AT, Dar AR, Whiston F, Stitt LW. Does sex influence the impact that smoking, treatment interruption and impaired pulmonary function have on outcomes in limited stage small cell lung cancer treatment? Can Respir J. 2005;12(5):245–50.CrossRefPubMedGoogle Scholar
  77. 77.
    Le Bescont A, Vitte AL, Debernardi A, Curtet S, Buchou T, Vayr J, de Reynies A, Ito A, Guardiola P, Brambilla C, Yoshida M, Brambilla E, Rousseaux S, Khochbin S. Receptor-independent ectopic activity of prolactin predicts aggressive lung tumors and indicates HDACi-based therapeutic strategies. Antioxid Redox Signal. 2015;23(1):1–14.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Chen S, Wu H, Lv N, Wang H, Wang Y, Tang Q, Shao H, Sun C. LncRNA CCAT2 predicts poor prognosis and regulates growth and metastasis in small cell lung cancer. Biomed Pharmacother. 2016;82:583–8.CrossRefPubMedGoogle Scholar
  79. 79.
    Rindi G, Klersy C, Inzani F, Fellegara G, Ampollini L, Ardizzoni A, Campanini N, Carbognani P, De Pas TM, Galetta D, Granone PL, Righi L, Rusca M, Spaggiari L, Tiseo M, Viale G, Volante M, Papotti M, Pelosi G. Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer. 2014;21(1):1–16.CrossRefPubMedGoogle Scholar
  80. 80.
    Naidoo J, Santos-Zabala ML, Iyriboz T, Woo KM, Sima CS, Fiore JJ, Kris MG, Riely GJ, Lito P, Iqbal A, Veach S, Smith-Marrone S, Sarkaria IS, Krug LM, Rudin CM, Travis WD, Rekhtman N, Pietanza MC. Large cell neuroendocrine carcinoma of the lung: Clinico-pathologic features, treatment, and outcomes. Clin Lung Cancer. 2016;17(5):e121–9.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Righi L, Volante M, Rapa I, Tavaglione V, Inzani F, Pelosi G, Papotti M. Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer. 2010;17(4):977–87.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Anatomic PathologyComplejo Hospitalario Universitario de Santiago, University of Santiago de CompostelaSantiago de CompostelaSpain
  2. 2.Complejo Hospitalario Universitario de OurenseOurenseSpain

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