Large cell carcinoma of the lung: A tumor in search of an author. A clinically oriented critical reappraisal

Lung Cancer

Volumn 87, Issue 3, 2015, Pages 226-231

  Pelosi, Giuseppe ^a,b   Barbareschi, Mattia ^c   Cavazza, Alberto ^d   Graziano, Paolo ^e   Rossi, Giulio ^f   Papotti, Mauro ^g  

^a NATIONAL CANCER INSTITUTE   (Italy)

^b UNIVERSITY OF MILAN   (Italy)

^c SANTA CHIARA HOSPITAL   (Italy)

^d S MARIA NUOVA HOSPITAL   (Italy)

^e CASA SOLLIEVO DELLA SOFFERENZA HOSPITAL   (Italy)

^f UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^g UNIVERSITY OF TURIN   (Italy)

Author keywords

Classification; Diagnosis; Genetic profile; Immunohistochemistry; Large cell carcinoma; Lung; Pathology

Indexed keywords

CYTOKERATIN 5; CYTOKERATIN 6; DESMOCOLLIN; MUCIN; THYROID TRANSCRIPTION FACTOR 1; TUMOR MARKER;

CANCER DIAGNOSIS; CELL DIFFERENTIATION; CYTOLOGY; DISEASE CLASSIFICATION; ELECTRON MICROSCOPY; HUMAN; IMMUNOHISTOCHEMISTRY; IMMUNOPHENOTYPING; LARGE CELL CARCINOMA; LUNG ADENOCARCINOMA; LUNG BIOPSY; NEUROENDOCRINE TUMOR; NEXT GENERATION SEQUENCING; NON SMALL CELL LUNG CANCER; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SMALL CELL LUNG CANCER; SQUAMOUS CELL LUNG CARCINOMA; ALGORITHM; CANCER GRADING; CARCINOMA, LARGE CELL; LUNG NEOPLASMS; MORTALITY; PROGNOSIS;

ALGORITHMS; CARCINOMA, LARGE CELL; HUMANS; IMMUNOHISTOCHEMISTRY; LUNG NEOPLASMS; NEOPLASM GRADING; NEUROENDOCRINE TUMORS; PROGNOSIS; TUMOR MARKERS, BIOLOGICAL;

EID: 84924066485     PISSN: 01695002     EISSN: 18728332     Source Type: Journal    
DOI: 10.1016/j.lungcan.2015.01.008     Document Type: Review

References (81)

1. World Health Organization classification of tumors. Tumors of the lung, pleura, thymus and heart 2004, IARC Press, Lyon. W.D. Travis, E. Brambilla, H.K. Muller-Hermelink, C.C. Harris (Eds.).
2. Nicholson S.A., Beasley M.B., Brambilla E., Hasleton P.S., Colby T.V., Sheppard M.N., et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 2002, 26:1184-1197.
3. Travis W.D., Brambilla E., Noguchi M., Nicholson A.G., Geisinger K., Yatabe Y., 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, 137:668-684.
4. World Health Organization The World Health Organization histologic typing of lung tumors, 2nd ed. Am J Clin Pathol 1982, 77:123-136.
5. Sholl L.M. Large-cell carcinoma of the lung: a diagnostic category redefined by immunohistochemistry and genomics. Curr Opin Pulm Med 2014, 20:324-331.
6. Weissferdt A. Large cell carcinoma of lung: On the verge of extinction?. Semin Diagn Pathol 2014, 31:278-288.
7. Scagliotti G.V., Parikh P., von Pawel J., Biesma B., Vansteenkiste J., Manegold C., et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008, 26:3543-3551.
8. Thunnissen E., Kerr K.M., Herth F.J., Lantuejoul S., Papotti M., Rintoul R.C., et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer 2012, 76:1-18.
9. Travis W.D., Brambilla E., Noguchi M., Nicholson A.G., Geisinger K.R., Yatabe Y., et al. The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol 2011, 6:244-285.
10. Rossi G., Marchioni A., Milani M., Scotti R., Foroni M., Cesinaro A., et al. TTF-1, cytokeratin 7, 34betaE12, and CD56/NCAM immunostaining in the subclassification of large cell carcinomas of the lung. Am J Clin Pathol 2004, 122:884-893.
11. Rekhtman N., Tafe L.J., Chaft J.E., Wang L., Arcila M.E., Colanta A., et al. Distinct profile of driver mutations and clinical features in immunomarker-defined subsets of pulmonary large-cell carcinoma. Mod Pathol 2013, 26:511-522.
12. Rossi G., Mengoli M.C., Cavazza A., Nicoli D., Barbareschi M., Cantaloni C., et al. Large cell carcinoma of the lung: clinically oriented classification integrating immunohistochemistry and molecular biology. Virchows Arch 2014, 464:61-68.
13. Rekhtman N., Ang D.C., Sima C.S., Travis W.D., Moreira A.L. 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, 24:1348-1359.
14. Cadioli A., Rossi G., Costantini M., Cavazza A., Migaldi M., Colby T.V. Lung cancer histologic and immunohistochemical heterogeneity in the era of molecular therapies: analysis of 172 consecutive surgically resected, entirely sampled pulmonary carcinomas. Am J Surg Pathol 2014, 38:502-509.
15. Travis W.D., Rekhtman N., Riley G.J., Geisinger K.R., Asamura H., Brambilla E. Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift. J Thorac Oncol 2010, 5:411-414.
16. Travis W.D., Linnoila R.I., Tsokos M.G., Hitchcock C.L., Cutler G.B., Nieman L., 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.
17. Rossi G., Cavazza A., Marchioni A., Longo L., Migaldi M., Sartori G., 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, 23:8774-8785.
18. Niho S., Kenmotsu H., Sekine I., Ishii G., Ishikawa Y., Noguchi M., 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.
19. Le Treut J., Sault M.C., Lena H., Souquet P.J., Vergnenegre A., Le Caer 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.
20. Peifer M., Fernández-Cuesta L., Sos M.L., George J., Seidel D., Kasper L.H., et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012, 44:1104-1110.
21. Fernandez-Cuesta L., Peifer M., Lu X., Sun R., Ozretić L., Seidel D., et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun 2014, 5:3518.
22. Buettner R., Wolf J., Thomas R.K. Lessons learned from lung cancer genomics: the emerging concept of individualized diagnostics and treatment. J Clin Oncol 2013, 31:1858-1865.
23. Pelosi G., Papotti M., Rindi G., Scarpa A. Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. Endocr Pathol 2014, 25:151-164.
24. Rossi G., Pelosi G., Barbareschi M., Graziano P., Cavazza A., Papotti M. Subtyping non-small cell lung cancer: relevant issues and operative recommendations for the best pathology practice. Int J Surg Pathol 2013, 21:326-336.
25. Bari M.F., Brown H., Nicholson A.G., Kerr K.M., Gosney J.R., Wallace W.A., et al. BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas. Histopathology 2014, 64:547-556.
26. Marchevsky A.M., Gal A.A., Shah S., Koss M.N. Morphometry confirms the presence of considerable nuclear size overlap between small cells and large cells in high-grade pulmonary neuroendocrine neoplasms. Am J Clin Pathol 2001, 116:466-472.
27. den Bakker M.A., Willemsen S., Grunberg K., Noorduijn L.A., van Oosterhout M.F., van Suylen R.J., et al. Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability. Histopathology 2010, 56:356-363.
28. Watanabe R., Ito I., Kenmotsu H., Endo M., Yamamoto N., Ohde Y., et al. Large cell neuroendocrine carcinoma of the lung: is it possible to diagnose from biopsy specimens?. Jpn J Clin Oncol 2013, 43:294-304.
29. Pelosi G., Rindi G., Travis W.D., Papotti M. Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol 2014, 9:273-284.
30. Swarts A.D.R., Speel E.J.M. Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim Biophys Acta 2012, 1826:3255-3271.
31. Nasgashio R., Sato Y., Matsumoto T., Kageyama T., Hattori M., Iyoda A., et al. The balance between the expressions of hASH1 and HES1 differs between large cell neuroendocrine carcinoma and small cell carcinoma of the lung. Lung Cancer 2011, 74:405-410.
32. Iyoda A., Hiroshima K., Toyozaki T., Haga Y., Fujisawa T., Ohwada H. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer 2001, 91:1992-2000.
33. Howe M.C., Chapman A., Kerr K., Dougal M., Anderson H., Hasleton P.S. Neuroendocrine differentiation in non-small cell lung cancer and its relation to prognosis and therapy. Histopathology 2005, 46:195-201.
34. Pelosi G., Pasini F., Sonzogni A., Maffini F., Maisonneuve P., Iannucci A., et al. Prognostic implications of neuroendocrine differentiation and hormone production in patients with Stage I nonsmall cell lung carcinoma. Cancer 2003, 97:2487-2497.
35. Hiroshima K., Iyoda A., Shibuya K., Toyozaki T., Haga Y., Fujisawa T., et al. Prognostic significance of neuroendocrine differentiation in adenocarcinoma of the lung. Ann Thorac Surg 2002, 73:1732-1735.
36. Sterlacci W., Fiegl M., Hilbe W., Auberger J., Mikuz G., Tzankov A. Clinical relevance of neuroendocrine differentiation in non-small cell lung cancer assessed by immunohistochemistry: a retrospective study on 405 surgically resected cases. Virchows Arch 2009, 455:125-132.
37. Pelosi G., Sonzogni A., De Pas T., Galetta D., Veronesi G., Spaggiari L., et al. Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol 2010, 18:103-120.
38. Ohashi K., Maruvka J.E., Michor F., Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 2013, 31:1070-1080.
39. Rossi G., Pelosi G., Graziano P., Barbareschi M., Papotti M. A reevaluation of the clinical significance of histological subtyping of non-small-cell lung carcinoma: diagnostic algorithms in the era of personalized treatments. Int J Surg Pathol 2009, 17:206-218.
40. Loo P.S., Thomas S.C., Nicolson M.C., Fyfe M.N., Kerr K.M. Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. J Thorac Oncol 2010, 5:442-447.
41. Nicholson A.G., Gonzalez D., Shah P., Pynegar M.J., Deshmukh M., Rice A., et al. Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis. J Thorac Oncol 2010, 5:436-441.
42. Travis W.D., Rekhtman N. Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing. Semin Respir Crit Care Med 2011, 32:22-31.
43. Righi L., Graziano P., Fornari A., Rossi G., Barbareschi M., Cavazza A., et al. Immunohistochemical subtyping of nonsmall cell lung cancer not otherwise specified in fine-needle aspiration cytology: a retrospective study of 103 cases with surgical correlation. Cancer 2011, 117:3416-3423.
44. Mukhopadhyay S., Katzenstein A.L. Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6. Am J Surg Pathol 2011, 35:15-25.
45. Pelosi G., Fabbri A., Bianchi F., Maisonneuve P., Rossi G., Barbareschi M., et al. DNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach. J Thorac Oncol 2012, 7:281-290.
46. Pelosi G., Sonzogni A., Viale G. The classification of lung carcinoma: time to change the morphology-based approach?. Int J Surg Pathol 2010, 18:161-172.
47. Rossi G., Tiseo M., Cavazza A., Colby T.V. Is immunohistochemistry always required to diagnose lung cancer?. Adv Anat Pathol 2013, 20:327-333.
48. Hwang D.H., Szeto D.P., Perry A.S., Bruce J.L., Sholl L.M. Pulmonary large cell carcinoma lacking squamous differentiation is clinicopathologically indistinguishable from solid-subtype adenocarcinoma. Arch Pathol Lab Med 2014, 138:626-635.
49. Matoso A., Singh K., Jacob R., Greaves W.O., Tavares R., Noble L., et al. Comparison of thyroid transcription factor-1 expression by 2 monoclonal antibodies in pulmonary and nonpulmonary primary tumors. Appl Immunohistochem Mol Morphol 2010, 18:142-149.
50. Ordonez N.G. Thyroid transcription factor-1 is not expressed in squamous cell carcinomas of the lung: an immunohistochemical study with review of the literature. Appl Immunohistochem Mol Morphol 2012, 20:525-530.
51. Siami K., McCluggage W.G., Ordonez N.G., Euscher E.D., Malpica A., Sneige N., et al. Thyroid transcription factor-1 expression in endometrial and endocervical adenocarcinomas. Am J Surg Pathol 2007, 31:1759-1763.
52. Ordonez N.G. Value of thyroid transcription factor-1 immunostaining in tumor diagnosis: a review and update. Appl Immunohistochem Mol Morphol 2012, 20:429-444.
53. Pelosi G., Rossi G., Cavazza A., Righi L., Maisonneuve P., Barbareschi M., et al. DeltaNp63 (p40) distribution inside lung cancer: a driver biomarker approach to tumor characterization. Int J Surg Pathol 2013, 21:229-239.
54. Bishop J.A., Teruya-Feldstein J., Westra W.H., Pelosi G., Travis W.D., Rekhtman N. p40 (DNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol 2012, 25:405-415.
55. Turner B.M., Cagle P.T., Sainz I.M., Fukuoka J., Shen S.S., Jagirdar J. Napsin A, a new marker for lung adenocarcinoma, is complementary and more sensitive and specific than thyroid transcription factor 1 in the differential diagnosis of primary pulmonary carcinoma: evaluation of 1674 cases by tissue microarray. Arch Pathol Lab Med 2012, 136:163-171.
56. Mukhopadhyay S., Katzenstein A.L.A. Comparison of monoclonal napsin A, polyclonal napsin A, and TTF-1 for determining lung origin in metastatic adenocarcinomas. Am J Clin Pathol 2012, 138:703-711.
57. Bishop J.A., Sharma R., Illei P.B. Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum Pathol 2010, 41:20-25.
58. Downey P., Cummins R., Moran M., Gulmann C. If it's not CK5/6 positive, TTF-1 negative it's not a squamous cell carcinoma of lung. APMIS 2008, 116:526-529.
59. Monica V., Ceppi P., Righi L., Tavaglione V., Volante M., Pelosi G., et al. Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung. Mod Pathol 2009, 22:709-717.
60. Gómez-Morales M., Cámara-Pulido M., Miranda-León M.T., Sanchez-Palencia A., Boyero L., Gomez-Capilla J.A., et al. Differential immunohistochemical localization of desmosomal plaque-related proteins in non-small-cell lung cancer. Histopathology 2013, 63:103-113.
61. Agackiran Y., Ozcan A., Akyurek N., Memis L., Findik G., Kaya S. Desmoglein-3 and Napsin A double stain, a useful immunohistochemical marker for differentiation of lung squamous cell carcinoma and adenocarcinoma from other subtypes. Appl Immunohistochem Mol Morphol 2012, 20:350-355.
62. Tsuta K., Tanabe Y., Yoshida A., Takahashi F., Maeshima A.M., Asamura H., et al. Utility of 10 immunohistochemical markers including novel markers (desmocollin-3, glypican 3, S100A2, S100A7, and Sox-2) for differential diagnosis of squamous cell carcinoma from adenocarcinoma of the lung. J Thorac Oncol 2011, 6:1190-1199.
63. Sholl L.M., Long K.B., Hornick J.L. Sox2 expression in pulmonary non-small cell and neuroendocrine carcinomas. Appl Immunohistochem Mol Morphol 2010, 18:55-61.
64. Chilosi M., Murer B. Mixed adenocarcinomas of the lung: place in new proposals in classification, mandatory for target therapy. Arch Pathol Lab Med 2010, 134:55-65.
65. Pelosi G., Melotti F., Cavazza A., Papotti M., Rossi G., Maisonneuve P., et al. A modified vimentin histological score helps recognize pulmonary sarcomatoid carcinoma in small biopsy samples. Anticancer Res 2012, 32:1463-1473.
66. Lazar V., Suo C., Orear C., van den Oord J., Balogh Z., Guegan J., et al. Integrated molecular portrait of non-small cell lung cancers. BMC Med Genomics 2013, 6:53.
67. Imielinski M., Berger A.H., Hammerman P.S., et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012, 14(150):1107-1120.
68. The Cancer Genome Network Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012, 489:519-523.
69. Barbareschi M., Cantaloni C., Del Vescovo V., Cavazza A., Monica V., Carella R., et al. Heterogeneity of large cell carcinoma of the lung: an immunophenotypic and miRNA-based analysis. Am J Clin Pathol 2011, 136:773-782.
70. Bishop J.A., Benjamin H., Cholakh H., Chajut A., Clark D.P., Westra W.H. Accurate classification of non-small cell lung carcinoma using a novel microRNA-based approach. Clin Cancer Res 2010, 16:610-619.
71. Monica V., Scagliotti G.V., Ceppi P., Righi L., Cambieri A., Lo Iacono M., et al. Differential thymidylate synthase expression in different variants of large-cell carcinoma of the lung. Clin Cancer Res 2009, 15:7547-7552.
72. Yashima H., Shimizu K., Araki T., Aomori T., Ohtaki Y., Nagashima T., et al. Assessment of DDR2, BRAF, EGFR and KRAS mutations as therapeutic targets in non-adenocarcinoma lung cancer patients. Mol Clin Oncol 2014, 2:714-718.
73. Yousem S.A. Immunohistochemical and molecular characterization of clear cell carcinoma of the lung. Hum Pathol 2013, 44:2467-2474.
74. Gainor J.F., Varghese A.M., Ou S.H., Kabraji S., Awad M.M., Katayama R., et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013, 19:4273-4281.
75. Jänne P.A., Shaw A.T., Pereira J.R., Jeannin G., Vansteenkiste J., Barrios C., et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013, 14:38-47.
76. Lindeman N.I., Cagle P.T., Beasley M.B., Chitale D.A., Dacic S., Giaccone G., College of American Pathologists International Association for the Study of Lung Cancer and Association for Molecular Pathology, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn 2013, 15:415-453.
77. Rekhtman N., Paik P.K., Arcila M.E., Tafe L.J., Oxnard G.R., Moreira A.L., et al. Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res 2012, 18:1167-1176.
78. Rossi G., Cavazza A. Histologic type definition in clinical trials on advanced non-small cell lung cancer. J Thorac Oncol 2011, 6:405.
79. Pelosi G., Haspinger E.R., Bimbatti M., Leone G., Paolini B., Fabbri A., et al. Does immunohistochemistry affect response to therapy and survival of inoperable non-small cell lung carcinoma patients? A survey of 145 stage III-IV consecutive cases. Int J Surg Pathol 2014, 22:136-148.
80. Righi L., Vavalà T., Rapa I., Vatrano S., Giorcelli J., Rossi G., et al. Impact of non-small cell lung cancer-not otherwise specified immunophenotyping on treatment outcome. J Thorac Oncol 2014, 9:1540-1549.
81. Davidson M.R., Gazdar A.F., Clarke B.E. The pivotal role of pathology in the management of lung cancer. J Thorac Dis 2013, 5(Suppl. 5):S463-S478.