Advertisement

Tumor Biology

, Volume 37, Issue 6, pp 7047–7057 | Cite as

Treatment of lung large cell neuroendocrine carcinoma

  • Giuseppe Lo Russo
  • Sara Pusceddu
  • Claudia Proto
  • Marianna Macerelli
  • Diego Signorelli
  • Milena Vitali
  • Monica Ganzinelli
  • Rosaria Gallucci
  • Nicoletta Zilembo
  • Marco Platania
  • Roberto Buzzoni
  • Filippo de Braud
  • Marina Chiara Garassino
Review

Abstract

Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I–II–III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.

Keywords

Large cell neuroendocrine carcinoma Lung neuroendocrine tumor Chemotherapy Treatment options 

Notes

Acknowledgments

The authors want to thank Luca Giacomelli for his valuable support in medical writing assistance.

Compliance with ethical standards

Conflict of interest

None

References

  1. 1.
    Travis WD, Rush W, Flieder DB, et al. 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;22:934–44.CrossRefPubMedGoogle Scholar
  2. 2.
    Iyoda A, Makino T, Koezuka S, et al. Treatment options for patients with large cell neuroendocrine carcinoma of the lung. Gen Thorac Cardiovasc Surg. 2014;62:351–6.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Su YH, Lin SW, Hsieh CC, et al. Treatment outcomes of patients with different subtypes of large cell carcinoma of the lung. Ann Thorac Surg. 2014;98:1013–9.CrossRefGoogle Scholar
  4. 4.
    Liang R, Chen TX, Wang ZQ, et al. A retrospective analysis of the clinicopathological characteristics of large cell carcinoma of the lung. Exp Ther Med. 2015;9:197–202.PubMedGoogle Scholar
  5. 5.
    Paci M, Cavazza A, Annessi V, et al. Large cell neuroendocrine carcinoma of the lung: a 10-year clinicopathologic retrospective study. Ann Thorac Surg. 2004;77:1163–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Battafarano RJ, Fernandez FG, Ritter J, et al. Large cell neuroendocrine carcinoma: an aggressive form of non-smallcell lung cancer. J Thorac Cardiovasc Surg. 2005;130:166–72.CrossRefPubMedGoogle Scholar
  7. 7.
    Veronesi G, Morandi U, Alloisio M, et al. Large cell neuroendocrine carcinoma of the lung: a retrospective analysis of 144surgical cases. Lung Cancer. 2006;53:111–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An Ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol. 1991;15:529–53.CrossRefPubMedGoogle Scholar
  9. 9.
    Travis WD, Corrin B, Shimosato Y, Brambilla E. Histological typing of lung and pleural tumors, in world health organization international histological classification of tumors. Berlin: Springer Verlag; 1999.CrossRefGoogle Scholar
  10. 10.
    Yao JC, Hassan M, Phan A, et al. 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;26:3063–72.CrossRefPubMedGoogle Scholar
  11. 11.
    Travis WD, Brambilla E, Muller-Hermelink H, Harris C. Tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004.Google Scholar
  12. 12.
    Travis WD, Brambilla E, Nicholson AG, et al. The 2015 world health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10:1243–60.CrossRefPubMedGoogle Scholar
  13. 13.
    Asamura H, Kameya T, Matsuno Y, et al. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol. 2006;24:70–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Schreiber G, McCrory D. Performance characteristics of different modalities for diagnosis of suspected lung cancer. Chest. 2003;123:115–28.CrossRefGoogle Scholar
  15. 15.
    Oshiro Y, Kusumoto M, Matsuno Y, et al. CT findings of surgically resected large cell neuroendocrine carcinoma of the lung in 38 patients. AJR Am J Roentgenol. 2004;182:87–91.CrossRefPubMedGoogle Scholar
  16. 16.
    Jung KJ, Lee KS, Han J, et al. Large cell neuroendocrine carcinoma of the lung: clinical, CT, and pathologic findings in 11 patients. J Thorac Imaging. 2001;16:156–62.CrossRefPubMedGoogle Scholar
  17. 17.
    Rivera MP, Mehta AC. Initial diagnosis of lung cancer. ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132:131–48.CrossRefGoogle Scholar
  18. 18.
    Varela-Lema L, Fernandez-Villar A, Ruano-Ravina A. Effectiveness and safety of endobronchial ultrasound-transbronchial needle aspiration: a systematic review. Eur Respir J. 2009;33:1156–64.CrossRefPubMedGoogle Scholar
  19. 19.
    Nakajima T, Yasufuku K. How I do it—optimal methodology for multidirectional analysis of endobronchial ultrasound-guided transbronchial needle aspiration samples. J Thorac Oncol. 2011;6:203–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Kaira K, Murakami H, Endo M, et al. Biological correlation of 18F-FDG uptake on PET in pulmonary neuroendocrine tumors. Anticancer Res. 2013;33:4219–28.PubMedGoogle Scholar
  21. 21.
    Detterbeck FC, Lewis SZ, Diekemper R, et al. Executive summary: diagnosis and management of lung cancer, 3rd ed. American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:7–37.CrossRefGoogle Scholar
  22. 22.
    Lee KW, Lee Y, Oh SW, et al. Large cell neuroendocrine carcinoma of the lung: CT and FDG PET findings. Eur J Radiol. 2015;84:2332–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Asamura H. Identity, similarity, and difference between large cell neuroendocrine carcinoma and small cell carcinoma. J Thorac Oncol. 2011;6:1774.CrossRefPubMedGoogle Scholar
  24. 24.
    Derks JL, Speel EM, Van Suylen RJ, Dingemans AM. Large Cell Neuroendocrine Carcinoma: How Accurate Are the WHO 2004 Classification Criteria Applied? WCLC 2015; abstract P1.08-024.Google Scholar
  25. 25.
    Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med. 2013;137:668–84.CrossRefPubMedGoogle Scholar
  26. 26.
    Maleki Z. Diagnostic issues with cytopathologic interpretation of lung neoplasms displaying highgrade basaloid or neuroendocrine morphology. Diagn Cytopathol. 2011;39:159–67.CrossRefPubMedGoogle Scholar
  27. 27.
    Iyoda A, Hiroshima K, Toyozaki T, et al. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer. 2001;91:1992–2000.CrossRefPubMedGoogle Scholar
  28. 28.
    Iyoda A, Hiroshima K, Moriya Y, et al. Pulmonary large cell neuroendocrine carcinoma demonstrates high proliferative activity. Ann Thorac Surg. 2004;77:1891–5.CrossRefPubMedGoogle Scholar
  29. 29.
    Iyoda A, Baba M, Hiroshima K, et al. Imprint cytologic features of pulmonary large cell neuroendocrin carcinoma: comparison with classic large cell carcinoma. Oncol Rep. 2004;11:285–8.PubMedGoogle Scholar
  30. 30.
    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;29:179–87.CrossRefPubMedGoogle Scholar
  31. 31.
    Rindi G, Klersy C, Inzani F, et al. Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer. 2014;21:1–16.CrossRefPubMedGoogle Scholar
  32. 32.
    Isaka M, Nakagawa K, Ohde Y, et al. A clinic-pathological study of peripheral, small-sized highgrade neuroendocrine tumours of the lung: differences between small-cell lung carcinoma and large-cell neuroendocrine carcinoma. Eur J Cardiothorac Surg. 2012;41:841–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Hiroshima K, Iyoda A, Shibuya K, et al. Genetic alterations in early-stage pulmonary large cell neuroendocrine carcinoma. Cancer. 2004;100:1190–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Zaffaroni N, De Polo D, Villa R, et al. Differential expression of telomerase activity in neuroendocrine lung tumours: correlation with gene product immunophenotyping. J Pathol. 2003;201:127–33.CrossRefPubMedGoogle Scholar
  35. 35.
    Peng WX, Shibata T, Katoh H, et al. Array-based comparative genomic hybridization analysis of high-grade neuroendocrine tumors of the lung. Cancer Sci. 2005;96:661–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Ullmann R, Petzmann S, Sharma A, et al. Chromosomal aberrations in a series of large-cell neuroendocrine carcinomas: unexpected divergence from small-cell carcinoma of the lung. Hum Pathol. 2001;32:1059–63.CrossRefPubMedGoogle Scholar
  37. 37.
    Nitadori J, Ishii G, Tsuta K, et al. Immunohistochemical differential diagnosis between large cell neuroendocrine carcinoma and small cell carcinoma by tissue microarray analysis with a large antibody panel. Am J Clin Pathol. 2006;125:682–92.CrossRefPubMedGoogle Scholar
  38. 38.
    Matsumura Y, Umemura S, Ishii G, et al. 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;141:2159–70.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Fernandez-Cuesta L, Peifer M, George J et al. Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors. WCLC 2015; abstract Oral 06.01.Google Scholar
  40. 40.
    Derks JL, Hendriks LE, Buikhuisen WA, et al. Clinical features of large cell neuroendocrine carcinoma: a population-based overview. Eur Respir J. 2016;47:615–24.CrossRefPubMedGoogle Scholar
  41. 41.
    Eichhorn F, Dienemann H, Muley T, et al. Predictors of survival after operation among patients with large cell neuroendocrine carcinoma of the lung. Ann Thorac Surg. 2015;99:983–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Iyoda A, Jiang SX, Travis WD, et al. Clinicopathological features and the impact of the new TNM classification of malignant tumors in patients with pulmonary large cell neuroendocrine carcinoma. Mol Clin Oncol. 2013;1:437–43.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Filosso PL, Rena O, Guerrera F, et al. Clinical management of atypical carcinoid and large-cell neuroendocrine carcinoma: a multicentre study on behalf of the European Association of Thoracic Surgeons (ESTS) Neuroendocrine Tumours of the Lung Working Group†. Eur J Cardiothorac Surg. 2015;48:55–64.CrossRefPubMedGoogle Scholar
  44. 44.
    Iyoda A, Hiroshima K, Moriya Y, et al. Prognostic impact of large cell neuroendocrine histology in patients with pathological stage 1a pulmonary non-small cell carcinoma. J Thorac Cardiovasc Surg. 2006;132:312–5.CrossRefPubMedGoogle Scholar
  45. 45.
    Glisson BS, Moran CA. Large-cell neuroendocrine carcinoma: controversies in diagnosis and treatment. J Natl Compr Canc Netw. 2011;9:1122–9.PubMedGoogle Scholar
  46. 46.
    Fournel L, Falcoz PE, Alifano M, et al. Surgical management of pulmonary large cell neuroendocrine carcinomas: a 10-year experience. Eur J CardioThorac Surg. 2013;43:111–4.CrossRefPubMedGoogle Scholar
  47. 47.
    Iyoda A, Hiroshima K, Toyozaki T, et al. Adjuvant chemotherapy for large cell carcinoma with neuroendocrine features. Cancer. 2001;92:1108–12.CrossRefPubMedGoogle Scholar
  48. 48.
    Kozuki T, Fujimoto N, Ueoka H, et al. Complexity in the treatment of pulmonary large cell neuroendocrine carcinoma. J Cancer Res Clin Oncol. 2005;131:147–51.CrossRefPubMedGoogle Scholar
  49. 49.
    Sakurai H, Asamura H. Large-cell neuroendocrine carcinoma of the lung surgical management. Thorac Surg Clin. 2014;24:305–11.CrossRefPubMedGoogle Scholar
  50. 50.
    Iyoda A, Hiroshima K, Moriya Y, et al. Prospective study of adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinoma. Ann Thorac Surg. 2006;82:1802–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Iyoda A, Hiroshima K, Moriya Y, et al. Postoperative recurrence and the role of adjuvant chemotherapy in patients with pulmonary large-cell neuroendocrine carcinoma. J Thorac Cardiovasc Surg. 2009;138:446–53.CrossRefPubMedGoogle Scholar
  52. 52.
    Rossi G, Cavazza A, Marchioni A, et al. Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFR alpha, PDGFR beta, and Met in large-cell neuroendocrine carcinoma of the lung. J Clin Oncol. 2005;23:8774–85.CrossRefPubMedGoogle Scholar
  53. 53.
    Saji H, Tsuboi M, Matsubayashi J, et al. Clinical response of large cell neuroendocrine carcinoma of the lung to perioperative adjuvant chemotherapy. Anticancer Drugs. 2010;21:89–93.CrossRefPubMedGoogle Scholar
  54. 54.
    Sarkaria IS, Iyoda A, Roh MS, et al. Neoadjuvant and adjuvant chemotherapy in resecate pulmonary large cell neuroendocrine carcinomas: a single institution experience. Ann Thorac Surg. 2011;92:1180–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Abedallaa N, Tremblay L, Baey C, et al. Effect of chemotherapy in patients with resected small-cell or large-cell neuroendocrine carcinoma. J Thorac Oncol. 2012;7:1179–83.CrossRefPubMedGoogle Scholar
  56. 56.
    Tanaka Y, Ogawa H, Uchino K, et al. Immunohistochemical studies of pulmonary large cell neuroendocrine carcinoma: a possible association between staining patterns with neuroendocrine markers and tumor response to chemotherapy. J Thorac Cardiovasc Surg. 2013;145:839–46.CrossRefPubMedGoogle Scholar
  57. 57.
    Kenmotsu H, Niho S, Ito T, et al. A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high-grade pulmonary neuroendocrine carcinoma (large cell neuroendocrine carcinoma and small cell lung cancer). Lung Cancer. 2014;84:254–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Eba J, Kenmotsu H, Tsuboi M, et al. Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group; Lung Cancer Study Group of the Japan Clinical Oncology Group. A Phase III trial comparing irinotecan and cisplatin with etoposide and cisplatin in adjuvant chemotherapy for completely resected pulmonary high-grade neuroendocrine carcinoma (JCOG1205/1206). Jpn J Clin Oncol. 2014;44:379–82.CrossRefPubMedGoogle Scholar
  59. 59.
    Mazières J, Daste G, Molinier L, et al. Large cell neuroendocrine carcinoma of the lung: pathological study and clinical outcome of 18 resected cases. Lung Cancer. 2002;37:287–92.CrossRefPubMedGoogle Scholar
  60. 60.
    Rieber J, Schmitt J, Warth A, et al. Outcome and prognostic factors of multimodal therapy for pulmonary large-cell neuroendocrine carcinomas. Eur J Med Res. 2015;20:64.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Ricciuti B, Metro G, Ferolla P, et al. Clinical outcome of platinum/etoposide treated large cell neuroendocrine carcinomas of the lung according to the type of radiotherapy received: a single institution analysis. Ann Oncol. 2015;26:78.CrossRefGoogle Scholar
  62. 62.
    Sun JM, Ahn MJ, Ahn JS, et al. Chemotherapy for pulmonary large cell neuroendocrine carcinoma: similar to that for small cell lung cancer or non-small cell lung cancer? Lung Cancer. 2012;77:365–70.CrossRefPubMedGoogle Scholar
  63. 63.
    Le Treut J, Sault MC, Lena H, et al. Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study. Ann Oncol. 2013;24:1548–52.CrossRefPubMedGoogle Scholar
  64. 64.
    Igawa S, Watanabe R, Ito I, et al. Comparison of chemotherapy for unresectable pulmonary high-grade non-small cell neuroendocrine carcinoma and small-cell lung cancer. Lung Cancer. 2010;68:438–45.CrossRefPubMedGoogle Scholar
  65. 65.
    Yamazaki S, Sekine I, Matsuno Y, et al. Clinical responses of large cell neuroendocrine carcinoma of the lung to cisplatin-based chemotherapy. Lung Cancer. 2005;49:217–23.CrossRefPubMedGoogle Scholar
  66. 66.
    Shimada Y, Niho S, Ishii G, et al. Clinical features of unresectable high-grade lung neuroendocrine carcinoma diagnosed using biopsy specimens. Lung Cancer. 2012;75:368–73.CrossRefPubMedGoogle Scholar
  67. 67.
    Tokito T, Kenmotsu H, Watanabe R, et al. Comparison of chemotherapeutic efficacy between LCNEC diagnosed using large specimens and possible LCNEC diagnosed using small biopsy specimens. Int J Clin Oncol. 2012;19:63–7.CrossRefPubMedGoogle Scholar
  68. 68.
    Fujiwara Y, Sekine I, Tsuta K, et al. Effect of platinum combined with irinotecan or paclitaxel against large cell neuroendocrine carcinoma of the lung. Jpn J Clin Oncol. 2007;37:482–6.CrossRefPubMedGoogle Scholar
  69. 69.
    Jiang J, Liang X, Zhou X, et al. A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer. J Thorac Oncol. 2010;5:867–73.CrossRefPubMedGoogle Scholar
  70. 70.
    Niho S, Kenmotsu H, Sekine I, et al. Combination chemotherapy with irinotecan and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicenter phase II study. J Thorac Oncol. 2013;8:980–4.CrossRefPubMedGoogle Scholar
  71. 71.
    Filosso PL, Ruffini E, Oliaro A, et al. Large-cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighteen cases and the efficacy of adjuvant treatment with octreotide. J Thorac Cardiovasc Surg. 2005;129:819–24.CrossRefPubMedGoogle Scholar
  72. 72.
    Yoshida H, Sekine I, Tsuta K, et al. Amrubicin monotherapy for patients with previously treated advanced large-cell neuroendocrin carcinoma of the lung. Jpn J Clin Oncol. 2011;41:897–901.CrossRefPubMedGoogle Scholar
  73. 73.
    Kenmotsu Y, Oshita F, Sugiura M, et al. Nedaplatin and irinotecan in patients with large-cell neuroendocrine carcinoma of the lung. Anticancer Res. 2012;32:1453–6.PubMedGoogle Scholar
  74. 74.
    Yoshida Y, Ota S, Murakawa T, et al. Combined large cell neuroendocrine carcinoma and adenocarcinoma with epidermal growth factor receptor mutation in a female patient who never smoked. Ann Thorac Cardiovasc Surg. 2014;20:582–4.CrossRefPubMedGoogle Scholar
  75. 75.
    De Pas TM, Giovannini M, Manzotti M, et al. Large-cell neuroendocrine carcinoma of the lung harboring EGFR mutation and responding to gefitinib. J Clin Oncol. 2011;29:819–22.CrossRefGoogle Scholar
  76. 76.
    Yanagisawa S, Morikawa N, Kimura Y, et al. Large-cell neuroendocrine carcinoma with epidermal growth factor receptor mutation: possible transformation of lung adenocarcinoma. Respirology. 2012;17:1275–7.CrossRefPubMedGoogle Scholar
  77. 77.
    Wang Y, Shen YH, Ma S, Zhou J. A marked response to icotinib in a patient with large cell neuroendocrine carcinoma harboring an EGFR mutation: a case report. Oncol Lett. 2015;10:1575–8.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Yokouchi H, Kitahashi M, Oshitari T, Yamamoto S. Intravitreal bevacizumab for iris tumor metastasized from large cell neuroendocrine carcinoma of lung. Graefes Arch Clin Exp Ophthalmol. 2013;251:2243–5.CrossRefPubMedGoogle Scholar
  79. 79.
    Iyoda A, Travis WD, Sarkaria IS, et al. Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma. Exp Ther Med. 2011;2:1041–5.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Odate S, Nakamura K, Onishi H, et al. TrkB/BDNF signaling pathway is a potential therapeutic target for pulmonary large cell neuroendocrine carcinoma. Lung Cancer. 2013;79:205–14.CrossRefPubMedGoogle Scholar
  81. 81.
    Odate S, Onishi H, Nakamura K, et al. Tropomyosin-related kinase B inhibitor has potential for tumor regression and relapse prevention in pulmonary large cell neuroendocrine carcinoma. Anticancer Res. 2013;33:3699–703.PubMedGoogle Scholar
  82. 82.
    Pelosi G, Barbareschi M, Cavazza A, et al. Large cell carcinoma of the lung: a tumor in search of an author. A clinically oriented critical reappraisal. Lung Cancer. 2015;87:226–31.CrossRefPubMedGoogle Scholar
  83. 83.
    Rossi G, Mengoli MC, Cavazza A, et al. Large cell carcinoma of the lung: clinically oriented classification integrating immunohistochemistry and molecular biology. Virchows Arch. 2014;464:61–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Varlotto JM, Medford-Davis LN, Recht A, et al. Should large cell neuroendocrine lung carcinoma be classified and treated as a small cell lung cancer or with other large cell carcinomas? J Thorac Oncol. 2011;6:1050–105.CrossRefPubMedGoogle Scholar
  85. 85.
    Fasano M, Della Corte CM, Papaccio F, et al. Pulmonary large-cell neuroendocrine carcinoma: from epidemiology to therapy. J Thorac Oncol. 2015;10:1133–41.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Masters GA, Temin S, Azzoli CG, et al. Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015;33:3488–515.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Giuseppe Lo Russo
    • 1
  • Sara Pusceddu
    • 1
  • Claudia Proto
    • 1
  • Marianna Macerelli
    • 1
  • Diego Signorelli
    • 1
  • Milena Vitali
    • 1
  • Monica Ganzinelli
    • 1
  • Rosaria Gallucci
    • 1
  • Nicoletta Zilembo
    • 1
  • Marco Platania
    • 1
  • Roberto Buzzoni
    • 1
  • Filippo de Braud
    • 1
  • Marina Chiara Garassino
    • 1
  1. 1.Department of Medical OncologyFondazione IRCCS, Istituto Nazionale dei TumoriMilanoItaly

Personalised recommendations