Pulmonary Large-Cell Neuroendocrine Carcinoma: From Epidemiology to Therapy

Morena Fasano, Carminia Maria Della Corte, Federica Papaccio, Fortunato Ciardiello, Floriana Morgillo, Morena Fasano, Carminia Maria Della Corte, Federica Papaccio, Fortunato Ciardiello, Floriana Morgillo

Abstract

Lung neuroendocrine tumors are a heterogeneous subtype of pulmonary cancers representing approximately 20% of all lung cancers, including small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). The frequency appears to be approximately 3% for LCNEC. Diagnosis of LCNEC requires attention to neuroendocrine features by light microscopy and confirmation by immunohistochemical staining for neuroendocrine markers. Both SCLC and pulmonary LCNEC are high-grade and poor-prognosis tumors, with higher incidence in males and smokers and peripheral localization. LCNEC is very rare, and the precise diagnosis on small specimens is very difficult, so we have still too few data to define a standard of treatment for pulmonary LCNECs. Data of literature, most based on retrospective analysis, indicated a poor 5-year overall survival, with a high incidence of recurrence after surgery, even in stage I disease. Primary surgery should be the first option in all operable patients because there is no validate therapeutic approach for LCNEC due to lack of clinical trials in this setting. Neoadjuvant platinum-based regimens remain only an option for potentially resectable tumors. In advanced stages, SCLC-like chemotherapy seems the best option of treatment, with a good response rate but a poor overall survival (from 8 to 16 months in different case series). New agents are under clinical investigation to improve LCNEC patients' outcome. We reviewed all data on treatment options feasible for pulmonary LCNEC, both for localized and extensive disease.

Conflict of interest statement

Disclosure: The authors declare no conflict of interest.

References

    1. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113:5–21.
    1. Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg. 1972;64:413–421.
    1. 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;15:529–553.
    1. Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134:1628–1638.
    1. 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;6:1050–1058.
    1. Younossian AB, Bründler MA, Tötsch M. Feasibility of the new WHO classification of pulmonary neuroendocrine tumours. Swiss Med Wkly. 2002;132:535–540.
    1. Fernandez FG, Battafarano RJ. Large-cell neuroendocrine carcinoma of the lung: an aggressive neuroendocrine lung cancer. Semin Thorac Cardiovasc Surg. 2006;18:206–210.
    1. Sánchez de Cos Escuín J. Diagnosis and treatment of neuroendocrine lung tumors. Arch Bronconeumol. 2014;50:392–396.
    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;22:934–944.
    1. Selvaggi G, Scagliotti GV. Histologic subtype in NSCLC: does it matter? Oncology (Williston Park) 2009;23:1133–1140.
    1. Asamura H, Kameya T, Matsuno Y, et al. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol. 2006;24:70–76.
    1. 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.
    1. Travis WD, Giroux DJ, Chansky K, et al. 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.
    1. Papotti M, Croce S, Bello M, et al. Expression of somatostatin receptor types 2, 3, and 5 in biopsies and specimens of human lung tumours. Virchows Arch. 2001;439:787–797.
    1. Rodrigues M, Traub-Weidinger T, Li S, et al. Comparison of 111In-DOTA-DPhe1-Tyr3-octreotideand 111In-DOTA-lanreotide scintigraphy and dosimetry in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2006;33:532–540.
    1. Travis WD, Brambilla E, Müller-Hermelink HK, et al. World Health Organization Classification of Tumours. Pathology & Genetics. Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004.
    1. Iyoda A, Hiroshima K, Nakatani Y, Fujisawa T. Pulmonary large cell neuroendocrine carcinoma: its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg. 2007;84:702–707.
    1. 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.
    1. 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;464:61–68.
    1. Battafarano RJ, Fernandez FG, Ritter J, et al. Large cell neuroendocrine carcinoma: an aggressive form of non-small cell lung cancer. J Thorac Cardiovasc Surg. 2005;130:166–172.
    1. Chen LC, Travis WD, Krug LM. Pulmonary neuroendocrine tumors: what (little) do we know? J Natl Compr Canc Netw. 2006;4:623–630.
    1. Pelosi G, Barbareschi M, Cavazza A, Graziano P, Rossi G, Papotti M. Large cell carcinoma of the lung: a tumor in search of an author. A clinically oriented critical reappraisal. Lung Cancer. 2015;87:226–231.
    1. 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;79:205–214.
    1. Carvalho L. Reclassifying bronchial-pulmonary carcinoma: differentiating histological type in biopsies by immunohistochemistry. Rev Port Pneumol. 2009;15:1101–1119.
    1. Onuki N, Wistuba II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer. 1999;85:600–607.
    1. The Clinical Lung Cancer Genome Project (CLCGP); Network Genomic Medicine (NGM) A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5:209–213.
    1. 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;125:682–692.
    1. 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;138:446–453.
    1. 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;1:437–443.
    1. Zacharias J, Nicholson AG, Ladas GP, Goldstraw P. Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection. Ann Thorac Surg. 2003;75:348–352.
    1. Grand B, Cazes A, Mordant P, et al. High grade neuroendocrine lung tumors: pathological characteristics, surgical management and prognostic implications. Lung Cancer. 2013;81:404–409.
    1. 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;37:287–292.
    1. 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;43:111–114.
    1. 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.
    1. Veronesi G, Morandi U, Alloisio M, et al. Large cell neuroendocrine carcinoma of the lung: a retrospective analysis of 144 surgical cases. Lung Cancer. 2006;53:111–115.
    1. Iyoda A, Hiroshima K, Moriya Y, et al. Prospective study of adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinoma. Ann Thorac Surg. 2006;82:1802–1807.
    1. 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;84:254–258.
    1. 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;44:379–382.
    1. Skov BG, Holm B, Erreboe A, Skov T, Mellemgaard A. ERCC1 and Ki67 in small cell lung carcinoma and other neuroendocrine tumors of the lung: distribution and impact on survival. J Thorac Oncol. 2010;5:453–459.
    1. Sarkaria IS, Iyoda A, Roh MS, et al. Neoadjuvant and adjuvant chemotherapy in resected pulmonary large cell neuroendocrine carcinomas: a single institution experience. Ann Thorac Surg. 2011;92:1180–1186.
    1. Rossi G, Cavazza A, Marchioni A, et al. Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFR β, PDGFR α, and Met in large-cell neuroendocrine carcinoma of the lung. J Clin Oncol. 2006;34:8775–8785.
    1. 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;37:482–486.
    1. Bonomi P, Kim K, Fairclough D, et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000;18:623–631.
    1. Noda K, Nishiwaki Y, Kawahara M, et al. Japan Clinical Oncology Group. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346:85–91.
    1. Kubota K, Watanabe K, Kunitoh H, et al. Japanese Taxotere Lung Cancer Study Group. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol. 2004;22:254–261.
    1. 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;68:438–445.
    1. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol. 2011;6:244–285.
    1. 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. 2014;19:63–67.
    1. Shimada Y, Niho S, Ishii G, et al. Clinical features of unresectable high-grade lung neuroendocrine carcinoma diagnosed using biopsy specimens. Lung Cancer. 2012;75:368–373.
    1. 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;77:365–370.
    1. Monica V, Scagliotti GV, Ceppi P, et al. Differential thymidylate synthase expression in different variants of large-cell carcinoma of the lung. Clin Cancer Res. 2009;15:7547–7552.
    1. Jalal S, Ansari R, Govindan R, et al. Pemetrexed in second line and beyond small cell lung cancer: a Hoosier Oncology Group phase II study. J Thorac Oncol. 2009;4:93–96.
    1. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589–1597.
    1. Moore AM, Einhorn LH, Estes D, et al. Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: a Hoosier Oncology Group phase II trial. Lung Cancer. 2006;52:93–97.
    1. 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;24:1548–1552.
    1. 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;8:980–984.
    1. Satouchi M, Kotani Y, Shibata T, et al. Phase III study comparing amrubicin plus cisplatin with irinotecan plus cisplatin in the treatment of extensive-disease small-cell lung cancer: JCOG 0509. J Clin Oncol. 2014;32:1262–1268.
    1. Yoshida H, Sekine I, Tsuta K, et al. Amrubicin monotherapy for patients with previously treated advanced large-cell neuroendocrine carcinoma of the lung. Jpn J Clin Oncol. 2011;41:897–901.
    1. Harada T, Oizumi S, Ito K, et al. Hokkaido Lung Cancer Clinical Study Group. A phase II study of amrubicin as a third-line or fourth-line chemotherapy for patients with non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0901. Oncologist. 2013;18:439–445.
    1. Sakai Y, Yamasaki T, Kusakabe Y, et al. Large-cell neuroendocrine carcinoma of lung with epidermal growth factor receptor (EGFR) gene mutation and co-expression of adenocarcinoma markers: a case report and review of the literature. Multidiscip Respir Med. 2013;8:47–53.
    1. 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;2:1041–1045.
    1. 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:e819–e822.
    1. Yanagisawa S, Morikawa N, Kimura Y, et al. Large-cell neuroendocrine carcinoma with EGFR mutation: possible transformation of lung adenocarcinoma. Respirology. 2012;17:1275–1277.
    1. Dimova I, Popivanov G, Djonov V. Angiogenesis in cancer—general pathways and their therapeutic implications. J BUON. 2014;19:15–21.
    1. Mairinger FD, Walter RF, Werner R, et al. Activation of angiogenesis differs strongly between pulmonary carcinoids and neuroendocrine carcinomas and is crucial for carcinoid tumorigenesis. J Cancer. 2014;5:465–471.
    1. Kim JW, Koh Y, Kim DW, et al. Clinical implications of VEGF, TGF-β1, and IL-1β in patients with advanced non-small cell lung cancer. Cancer Res Treat. 2013;45:325–333.
    1. Liu B, Liu Q, Song Y, et al. Polymorphisms of HIF1A gene are associated with prognosis of early stage non-small-cell lung cancer patients after surgery. Med Oncol. 2014;31:877–886.
    1. Kenmotsu Y, Oshita F, Sugiura M, et al. Nedaplatin and irinotecan in patients with large-cell neuroendocrine carcinoma of the lung. Anticancer Res. 2012;32:1453–1456.
    1. Przygodzki RM, Finkelstein SD, Langer JC, et al. Analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumors. Correlation with histological subtype and clinical outcome. Am J Pathol. 1996;148:1531–1541.
    1. Hiroshima K, Iyoda A, Shibuya K, et al. Genetic alterations in early-stage pulmonary large cell neuroendocrine carcinoma. Cancer. 2004;100:1190–1198.
    1. 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;129:819–824.
    1. 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;49:217–223.
    1. Snider JW, III, Gondi V, Brown PD, Tome W, Mehta MP. Prophylactic cranial irradiation: recent outcomes and innovations. CNS Oncol. 2014;3:219–230.

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