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Published online: 2024-07-04

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Pulmonary large cell neuroendocrine carcinoma — diagnostic and therapeutic clinical dilemmas

Katarzyna Stencel1, Maciej Bryl1, Renata Langfort2
DOI: 10.5603/ocp.100360

Abstract

Pulmonary large cell neuroendocrine carcinoma (LCNEC) belongs to a heterogeneous group of lung cancers that show morphological, ultrastructural, and immunohistochemical similarities but differ in etiopathogenesis, molecular profile, clinical course, prognosis, and treatment. 

The prognosis for pulmonary LCNEC is extremely poor, and median overall survival usually does not exceed one year. According to the 2015 classification of the World Health Organization, LCNECs belong to neuroendocrine tumors, along with typical and atypical carcinoid tumors and small cell lung cancer (SCLC). The optimal therapeutic approach in LCNEC patients has not yet been determined. Accurate LCNEC diagnosis is crucial, and management algorithms should be developed on the basis of multicenter prospective clinical trials. 

This review presents the diagnosing criteria for large cell neuroendocrine carcinoma and reviews the effectiveness of available therapeutic options.

Keywords: large cell neuroendocrine carcinomachromogranin AsynaptophysinNCAM/CD56

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References

  1. WHO Classification of Tumours Editorial Board. Thoracic tumours. WHO classification of tumours series, 5th ed., vol. 5. International Agency for Research on Cancer, Lyon 2021.
  2. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018; 31(12): 1770–1786.
    CrossRefPubMed
  3. Kreyberg L, Liebow AA, Uehlinger EA. Histological typing of lung tumors. World Health Organization, Geneva 1967.
  4. The World Health Organization Histological Typing of Lung Tumours: Second Edition. Am J Clin Pathol. 1982; 77(2): 123–136.
    CrossRef
  5. Hirsch FR, Matthews MJ, Aisner S, et al. Histopathologic classification of small cell lung cancer. Changing concepts and terminology. Cancer. 1988; 62(5): 973–977, doi: 10.1002/1097-0142(19880901)62:5<973::aid-cncr2820620521>3.0.co;2-o.
    PubMed
  6. Yesner R. Classification of lung-cancer histology. N Engl J Med. 1985; 312(10): 652–653.
    CrossRefPubMed
  7. Travis WD, Colby TV, Corrin B, et al. Histological Typing of Lung and Pleural Tumours. Springer, Berlin, Heidelberg 1999.
  8. Travis WD. World Health Organization. Pathology and genetics of tumours of the lung, pleura, thymus and heart. IARC Press, Lyon 2004.
  9. Travis WD, Brambilla E, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon 2015.
  10. Vocino Trucco G, Righi L, Volante M, et al. Updates on lung neuroendocrine neoplasm classification. Histopathology. 2024; 84(1): 67–85.
    CrossRefPubMed
  11. Rekhtman N. Lung neuroendocrine neoplasms: recent progress and persistent challenges. Mod Pathol. 2022; 35(Suppl 1): 36–50.
    CrossRefPubMed
  12. Rekhtman N, Pietanza MC, Hellmann MD, et al. Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets. Clin Cancer Res. 2016; 22(14): 3618–3629.
    CrossRefPubMed
  13. Baine MK, Rekhtman N. Multiple faces of pulmonary large cell neuroendocrine carcinoma: update with a focus on practical approach to diagnosis. Transl Lung Cancer Res. 2020; 9(3): 860–878.
    CrossRefPubMed
  14. Takei H, Asamura H, Maeshima A, et al. Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty-seven cases. J Thorac Cardiovasc Surg. 2002; 124(2): 285–292.
    CrossRefPubMed
  15. 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(11): 1992–2000, doi: 10.1002/1097-0142(20010601)91:11<1992::aid-cncr1224>3.0.co;2-5.
    PubMed
  16. 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(6): 529–553.
    CrossRefPubMed
  17. Zou L, Guo T, Ye L, et al. Outcomes for Surgery in Stage IA Large Cell Lung Neuroendocrine Compared With Other Types of Non-Small Cell Lung Cancer: A Propensity Score Matching Study Based on the Surveillance, Epidemiology, and End Results (SEER) Database. Front Oncol. 2020; 10: 572462.
    CrossRefPubMed
  18. Ferrara MG, Stefani A, Simbolo M, et al. Large Cell Neuro-Endocrine Carcinoma of the Lung: Current Treatment Options and Potential Future Opportunities. Front Oncol. 2021; 11: 650293.
    CrossRefPubMed
  19. Zhuo M, Guan Y, Yang X, et al. The Prognostic and Therapeutic Role of Genomic Subtyping by Sequencing Tumor or Cell-Free DNA in Pulmonary Large-Cell Neuroendocrine Carcinoma. Clin Cancer Res. 2020; 26(4): 892–901.
    CrossRefPubMed
  20. Hiroshima K, Mino-Kenudson M. Update on large cell neuroendocrine carcinoma. Transl Lung Cancer Res. 2017; 6(5): 530–539.
    CrossRefPubMed
  21. Rossi G, Cavazza A, Marchioni A, et al. Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFRalpha, PDGFRbeta, and Met in large-cell neuroendocrine carcinoma of the lung. J Clin Oncol. 2005; 23(34): 8774–8785.
    CrossRefPubMed
  22. Iyoda A, Hiroshima K, Moriya Y, et al. Prognostic impact of large cell neuroendocrine histology in patients with pathologic stage Ia pulmonary non-small cell carcinoma. J Thorac Cardiovasc Surg. 2006; 132(2): 312–315.
    CrossRefPubMed
  23. Hiroshima K, Iyoda A, Shida T, et al. Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis. Mod Pathol. 2006; 19(10): 1358–1368.
    CrossRefPubMed
  24. Derks JL, Leblay N, Thunnissen E, et al. PALGA-Group. Molecular Subtypes of Pulmonary Large-cell Neuroendocrine Carcinoma Predict Chemotherapy Treatment Outcome. Clin Cancer Res. 2018; 24(1): 33–42.
    CrossRefPubMed
  25. Simbolo M, Barbi S, Fassan M, et al. Gene Expression Profiling of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Transcriptomic Subtypes with Specific Genomic Alterations. J Thorac Oncol. 2019; 14(9): 1651–1661.
    CrossRefPubMed
  26. George J, Walter V, Peifer M, et al. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 2018; 9(1): 1048.
    CrossRefPubMed
  27. Prieto TG, Baldavira CM, Machado-Rugolo J, et al. Clinical and morphological features of large-cell neuroendocrine carcinomas and small-cell lung carcinomas expressing the DLL3 and ASCL1 oncoproteins. Braz J Med Biol Res. 2023; 56: e12921.
    CrossRefPubMed
  28. 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(34): e819–e822.
    CrossRefPubMed
  29. Aroldi F, Bertocchi P, Meriggi F, et al. Tyrosine Kinase Inhibitors in EGFR-Mutated Large-Cell Neuroendocrine Carcinoma of the Lung? A Case Report. Case Rep Oncol. 2014; 7(2): 478–483.
    CrossRefPubMed
  30. Omachi N, Shimizu S, Kawaguchi T, et al. A case of large-cell neuroendocrine carcinoma harboring an EML4-ALK rearrangement with resistance to the ALK inhibitor crizotinib. J Thorac Oncol. 2014; 9(6): e40–e42.
    CrossRefPubMed
  31. Karlsson A, Brunnström H, Lindquist KE, et al. Mutational and gene fusion analyses of primary large cell and large cell neuroendocrine lung cancer. Oncotarget. 2015; 6(26): 22028–22037.
    CrossRefPubMed
  32. Miyoshi T, Umemura S, Matsumura Y, et al. Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung. Clin Cancer Res. 2017; 23(3): 757–765.
    CrossRefPubMed
  33. Derks JL, van Suylen RJ, Thunnissen E, et al. PALGA group. Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter? Eur Respir J. 2017; 49(6).
    CrossRefPubMed
  34. Iyoda A, Hiroshima K, Moriya Y, et al. Prospective study of adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinoma. Ann Thorac Surg. 2006; 82(5): 1802–1807.
    CrossRefPubMed
  35. 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(1): 111–115.
    CrossRefPubMed
  36. 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(4): 1180–6; discussion 1186.
    CrossRefPubMed
  37. 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(2): 365–370.
    CrossRefPubMed
  38. 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(3): 438–445.
    CrossRefPubMed
  39. 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(7): 482–486.
    CrossRefPubMed
  40. 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(7): 980–984.
    CrossRefPubMed
  41. 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(6): 1548–1552.
    CrossRefPubMed
  42. Christopoulos P, Engel-Riedel W, Grohé C, et al. Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial. Ann Oncol. 2017; 28(8): 1898–1902.
    CrossRefPubMed
  43. Naidoo J, Santos-Zabala ML, Iyriboz T, et al. Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes. Clin Lung Cancer. 2016; 17(5): e121–e129.
    CrossRefPubMed
  44. Eichhorn F, Harms A, Warth A, et al. PD-L1 expression in large cell neuroendocrine carcinoma of the lung. Lung Cancer. 2018; 118: 76–82.
    CrossRefPubMed
  45. Arpin D, Charpentier MC, Bernardi M, et al. PD-L1-expression patterns in large-cell neuroendocrine carcinoma of the lung: potential implications for use of immunotherapy in these patients: the GFPC 03-2017 "EPNEC" study. Ther Adv Med Oncol. 2020; 12: 1758835920937972.
    CrossRefPubMed
  46. Hermans BCM, Derks JL, Thunnissen E, et al. PALGA-group. Prevalence and prognostic value of PD-L1 expression in molecular subtypes of metastatic large cell neuroendocrine carcinoma (LCNEC). Lung Cancer. 2019; 130: 179–186.
    CrossRefPubMed
  47. Inamura K, Yokouchi Y, Kobayashi M, et al. Relationship of tumor PD-L1 (CD274) expression with lower mortality in lung high-grade neuroendocrine tumor. Cancer Med. 2017; 6(10): 2347–2356.
    CrossRefPubMed
  48. Levra M, Mazieres J, Valette C, et al. P1.07-012 Efficacy of Immune Checkpoint Inhibitors in Large Cell Neuroendocrine Lung Cancer: Results from a French Retrospective Cohort. J Thorac Oncol. 2017; 12(1): S702–S703.
    CrossRef
  49. Agar C, Geier M, Léveiller G, et al. Brief Report on the Efficacy of Nivolumab in Patients With Previously Treated Advanced Large-Cell Neuroendocrine Cancer of the Lung. JTO Clin Res Rep. 2021; 2(4): 100129.
    CrossRefPubMed
  50. Komiya T, Ravindra N, Powell E. Role of Immunotherapy in Stage IV Large Cell Neuroendocrine Carcinoma of the Lung. Asian Pac J Cancer Prev. 2021; 22(2): 365–370.
    CrossRefPubMed
  51. Dudnik E, Kareff S, Moskovitz M, et al. Israel Lung Cancer Group. Real-world survival outcomes with immune checkpoint inhibitors in large-cell neuroendocrine tumors of lung. J Immunother Cancer. 2021; 9(2).
    CrossRefPubMed
  52. www.clinicaltrials.gov.
  53. Buium C, Negru S, Ionescu DN, et al. The Unmet Diagnostic and Treatment Needs in Large Cell Neuroendocrine Carcinoma of the Lung. Curr Oncol. 2023; 30(8): 7218–7228.
    CrossRefPubMed
  54. Kim C, McGrath J, Xiu J, et al. Genomic and immunologic characteriation of large-cell neuroendocrine carcinoma of the lung. J Clin Oncol. 2021; 39(15_suppl).
    CrossRef
  55. Kobayashi T, Uehara Y, Watanabe K, et al. Successful Treatment of ALK-Positive Large-Cell Neuroendocrine Carcinoma of the Lung With Sequential ALK Inhibitors: A Case Report. JTO Clin Res Rep. 2023; 4(7): 100538.
    CrossRefPubMed
  56. Wiedemann C, Kazdal D, Cvetkovic J, et al. Lorlatinib and compound mutations in ALK+ large-cell neuroendocrine lung carcinoma: a case report. Cold Spring Harb Mol Case Stud. 2022; 8(6).
    CrossRefPubMed
  57. Gromowsky MJ, D'Angelo CR, Lunning MA, et al. ALK-positive anaplastic large cell lymphoma in adults. Fac Rev. 2023; 12: 21.
    CrossRefPubMed

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