Abstract
Large-cell (undifferentiated) carcinoma (LCC) and large-cell neuroendocrine (NE) carcinoma of the lung (LCNEC) are rare, poorly differentiated carcinomas defined by their histologic features, immunohistochemical (IHC) staining patterns, electron microscopy (EM) findings, and molecular pathway alterations. Traditionally, lung carcinomas are broadly classified as small-cell carcinoma (SCLC) and non-SCLC (NSCLC) based on morphological features. Both LCC and LCNEC are composed of malignant cells with NSCLC morphology, including large cells, low nuclear/cytoplasmic (N/C) ratio, vesicular chromatin, and prominent nucleoli. LCNEC has morphological and immunophenotypic features that demonstrate NE morphology, such as peripheral palisading, nesting, trabecular growth pattern, and rosette formation, as well as expression of one or more NE markers including chromogranin, synaptophysin, and CD56. NE secretory granules may also be seen on electron microscopy. Recent investigations have shown that insulinoma-associated protein 1 (INSM1) and human achaete-scute homolog-1 (hASH1 or ASCL1) are additional valuable markers of NE differentiation. LCC is considered an undifferentiated carcinoma, lacking morphological and immunohistochemical features of squamous cell carcinoma, adenocarcinoma, or NE carcinoma. To diagnose LCNEC, both NE morphology and NE differentiation are required. Past and existing literature has been confusing as different criteria have been used to diagnose LCNEC and LCC. A logical stepwise algorithm based on morphology and special studies is detailed in this chapter to differentiate LCC from LCNEC and other lung tumors using the new WHO classification.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Nicholson AG, Beasley MB, Caporaso NE, Carvalho L, Dalurzo ML, Devesa SS, et al. Large cell carcinoma. In: Travis WDBE, Burke AP, Marx A, Nicholson AG, editors. WHO classification of Tumours of of the lung, pleura, thymus and heart. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC); 2015. p. 80–5.
Rekhtman N, Ang DC, Sima CS, et al. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol. 2011;24:1348.
Pelosi G, Fabbri A, Papotti M, et al. Dissecting pulmonary large-cell carcinoma by targeted next generation sequencing of several cancer genes pushes genotypic-phenotypic correlations to emerge. J Thorac Oncol. 2015;10(11):1560–9.
Brambilla EBM, Chirieac LR, Austin JHM, Capelozzi VL, Devesa SS, Gazdar A, et al. Large cell neuroendocrine carcinoma. In: Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, editors. WHO classification of Tumours of of the lung, pleura, thymus and heart. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC); 2015. p. 69–72.
Ionescu DN, Treaba D, Gilks CB, et al. Nonsmall cell lung carcinoma with neuroendocrine differentiation--an entity of no clinical or prognostic significance. Am J Surg Pathol. 2007;31(1):26–32.
Ye B, Cappel J, Findeis-Hosey J, et al. hASH1 is a specific immunohistochemical marker for lung neuroendocrine tumors. Human Pathol. 2016;48:142–7.
Howe MC, Chapman A, Kerr K, et al. Neuroendocrine differentiation in non-small cell lung cancer and its relation to prognosis and therapy. Histopathology. 2005;46(2):195–201.
Pelosi G, Pasini F, Sonzogni A, et al. Prognostic implications of neuroendocrine differentiation and hormone production in patients with stage I nonsmall cell lung carcinoma. Cancer. 2003;97(10):2487–97.
Mukhopadhyay S, Dermawan JK, Lanigan CP, et al. Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol. 2019;32(1):100–9.
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(6):1050–8.
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.
Asamura H, Kameya T, Matsuno Y, et al. Neuroendocrine neoplasms of the lung: a prognostic Spectrum. J Clin Oncol. 2006;24(1):70–6.
Rossi G, Cavazza A, Marchioni A, et al. Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFRα, PDGFRβ, and met in large-cell neuroendocrine carcinoma of the lung. J Clin Oncol. 2005;23(34):8774–85.
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):1802–7.
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):e121–9.
Derks JL, van Suylen RJ, Thunnissen E, et al. Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter? Eur Resp J. 2017;49(6):1601838.
The clinical lung cancer genome project (CLCGP) and network genomic medicine (NGM). A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5(209):209ra153.
Karlsson A, Brunnström H, Micke P, et al. Gene expression profiling of large cell lung cancer links transcriptional phenotypes to the new histological WHO 2015 classification. J Thorac Oncol. 2017;12(8):1257–67.
Driver BR, Portier BP, Mody DR, et al. Next-generation sequencing of a cohort of pulmonary large cell carcinomas reclassified by World Health Organization 2015 criteria. Arch Pathol Lab Med. 2016;140(4):312–7.
Miyoshi T, Umemura S, Matsumura Y, et al. Genomic profiling of large-cell neuroendocrine carcinoma of the lung. Clin Cancer Res. 2017;23(3):757–65.
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):3618–29.
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.
Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO classification of Tumours of of the lung, pleura, thymus and heart. Lyon, France: International Agency for Research on Cancer (IARC); 2015.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Rothrock, A.T., Najmuddin, M., Li, F. (2022). Large-Cell (Undifferentiated) Carcinoma (LCC) Versus Large-Cell Neuroendocrine Carcinoma (LCNEC). In: Xu, H., Ricciotti, R.W., Mantilla, J.G. (eds) Practical Lung Pathology. Practical Anatomic Pathology. Springer, Cham. https://doi.org/10.1007/978-3-031-14402-8_12
Download citation
DOI: https://doi.org/10.1007/978-3-031-14402-8_12
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-14401-1
Online ISBN: 978-3-031-14402-8
eBook Packages: MedicineMedicine (R0)