Large cell carcinoma of the lung – a vanishing entity?

Short review
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Summary

There are four major types of lung carcinomas, small cell neuroendocrine carcinoma, squamous cell carcinoma, adenocarcinoma and large cell carcinomas (LC) [1]. Since the mid nineties the incidence of adenocarcinomas has increased; whereas squamous and small cell carcinomas have decreased dramatically [2, 3]. LC, however, remained constant at about 10–12% of all lung carcinomas. However, LC should not be mixed with large cell carcinoma variants including large cell neuroendocrine carcinoma, clear cell carcinoma, rhabdoid large cell carcinoma, basaloid, and lymphoepithelioma-like carcinoma, respectively. Whereas a lot of published data do exist for the LC variants, only few studies have investigated LC itself. Due to an increased use of differentiation markers in the diagnostic practice LC seems to decrease in frequency, and might even vanish. This review will try to explain the problems of LC diagnosis, the false use of this diagnosis, and reasons why LC is becoming a rare entity.

Keywords

Large cell carcinoma Immunohistochemistry Differentiation markers Targeted therapy Large cell carcinoma variants 
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References

  1. Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC. Pathology and Genetics of tumours of the lung, pleura, thymus and heart, Vol. 10. IARC WHO Classification of Tumours, IARC Press, Lyon, France, 2004Google Scholar
  2. Wynder EL, Muscat JE. The changing epidemiology of smoking and lung cancer histology, Environ Health Perspect, 103(Suppl. 8): 143–148, 1995PubMedCrossRefGoogle Scholar
  3. Thun MJ, Lally CA, Flannery JT, Calle EE, Flanders WD, Heath CW Jr. Cigarette smoking and changes in the histopathology of lung cancer. J Natl Cancer Inst, 89: 1580–1586, 1997PubMedCrossRefGoogle Scholar
  4. Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB, Nieman L, Chrousos G, Pass H, Doppman J. 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, 15: 529–553, 1991PubMedCrossRefGoogle Scholar
  5. Forgacs E, Zochbauer-Muller S, Olah E, Minna JD. Molecular genetic abnormalities in the pathogenesis of human lung cancer. Pathol Oncol Res, 7: 6–13, 2001PubMedCrossRefGoogle Scholar
  6. Osada H, Takahashi T. Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer. Oncogene 21: 7421–7434, 2002PubMedCrossRefGoogle Scholar
  7. Borczuk AC, Gorenstein L, Walter KL, Assaad AA, Wang L, Powell CA. Non-small-cell lung cancer molecular signatures recapitulate lung developmental pathways. Am J Pathol, 163: 1949–1960, 2003PubMedCrossRefGoogle Scholar
  8. Sy SM, Wong N, Lee TW, Tse G, Mok TS, Fan B, Pang E, Johnson PJ, Yim A. Distinct patterns of genetic alterations in adenocarcinoma and squamous cell carcinoma of the lung. Eur J Cancer, 40: 1082–1094, 2004PubMedCrossRefGoogle Scholar
  9. Kang JU, Koo SH, Kwon KC, Park JW, Kim JM. Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2–q29 in squamous cell carcinoma of the lung. BMC Cancer, 9: 237, 2009PubMedCrossRefGoogle Scholar
  10. Mascaux C, Laes JF, Anthoine G, Haller A, Ninane V, Burny A, Sculier JP. Evolution of microRNA expression during human bronchial squamous carcinogenesis, Eur Respir J, 33: 352–359, 2009PubMedCrossRefGoogle Scholar
  11. Bjorkqvist AM, Tammilehto L, Nordling S, Nurminen M, Anttila S, Mattson K, Knuutila S. Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung Br J Cancer, 77: 260–269, 1998PubMedCrossRefGoogle Scholar
  12. Franklin WA, Veve R, Hirsch FR, Helfrich BA, Bunn PA Jr. Epidermal growth factor receptor family in lung cancer and premalignancy, Semin Oncol, 29: 3–14, 2002PubMedCrossRefGoogle Scholar
  13. Dziadziuszko R, Merrick DT, Witta SE, Mendoza AD, Szostakiewicz B, Szymanowska A, Rzyman W, Dziadziuszko K, Jassem J, Bunn PA Jr, Varella-Garcia M, Hirsch FR. Insulin-like growth factor receptor 1 (IGF1R) gene copy number is associated with survival in operable non-small-cell lung cancer: a comparison between IGF1R fluorescent in situ hybridization, protein expression, and mRNA expression. J Clin Oncol, 28: 2174–2180, 2010PubMedCrossRefGoogle Scholar
  14. Ludovini V, Bellezza G, Pistola L, Bianconi F, Di Carlo L, Sidoni A, Semeraro A, Del Sordo R, Tofanetti FR, Mameli MG, Daddi G, Cavaliere A, Tonato M, Crino L. High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients. Ann Oncol, 20: 842–849, 2009PubMedCrossRefGoogle Scholar
  15. Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S, Chella A, Camplese PP, Iarussi T, Mucilli F, Mezzetti A, Cuccurullo F, Sacco R, Buttitta F. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol, 23: 857–865, 2005PubMedCrossRefGoogle Scholar
  16. Pardo J, Martinez-Penuela AM, Sola JJ, Panizo A, Gurpide A, Martinez-Penuela JM, Lozano MD. Large cell carcinoma of the lung: an endangered species? Appl Immunohistochem Mol Morphol, 17: 383–392, 2009PubMedCrossRefGoogle Scholar
  17. Hanagiri T, Oka S, Takenaka S, Baba T, Yasuda M, Ono K, So T, Uramoto H, Takenoyama M, Yasumoto K. Results of surgical resection for patients with large cell carcinoma of the lung. Int J Surg, 8: 391–394, 2010PubMedCrossRefGoogle Scholar
  18. Conde E, Angulo B, Redondo P, Toldos O, Garcia-Garcia E, Suarez-Gauthier A, Rubio-Viqueira B, Marron C, Garcia-Lujan R, Sanchez-Cespedes M, Lopez-Encuentra A, Paz-Ares L, Lopez-Rios F. The use of P63 immunohistochemistry for the identification of squamous cell carcinoma of the lung. PLoS One, 5: e12209, 2010PubMedCrossRefGoogle Scholar
  19. Monica V, Ceppi P, Righi L, Tavaglione V, Volante M, Pelosi G, Scagliotti GV, Papotti M. Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung, Mod Pathol, 22: 709–717, 2009PubMedCrossRefGoogle Scholar
  20. Ring BZ, Seitz RS, Beck RA, Shasteen WJ, Soltermann A, Arbogast S, Robert F, Schreeder MT, Ross DT. A novel five-antibody immunohistochemical test for subclassification of lung carcinoma, Mod Pathol, 22: 1032–1043, 2009PubMedCrossRefGoogle Scholar
  21. Hammar SP, Bolen JW, Bockus D, Remington F, Friedman S: Ultrastructural and immunohistochemical features of common lung tumors: an overview. Ultrastruct Pathol, 9: 283–318, 1985PubMedCrossRefGoogle Scholar
  22. Moll R, Cowin P, Kapprell HP, Franke WW. Desmosomal proteins: new markers for identification and classification of tumors, Lab Invest, 54: 4–25, 1986PubMedGoogle Scholar
  23. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new world health organization classification of lung tumours. Eur Respir J, 18: 1059–1068, 2001PubMedCrossRefGoogle Scholar
  24. Au NH, Gown AM, Cheang M, Huntsman D, Yorida E, Elliott WM, Flint J, English J, Gilks CB. Grimes HL: P63 expression in lung carcinoma: a tissue microarray study of 408 cases, Appl Immunohistochem Mol Morphol, 12: 240–247, 2004PubMedGoogle Scholar
  25. Petersen S, Heckert C, Rudolf J, Schluns K, Tchernitsa OI, Schafer R, Dietel M, Petersen I. Gene expression profiling of advanced lung cancer. Int J Cancer, 86: 512–517, 2000PubMedCrossRefGoogle Scholar
  26. Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ, Meyerson M. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses, Proc Natl Acad Sci USA, 98: 13790–13795, 2001PubMedCrossRefGoogle Scholar
  27. Heighway J, Knapp T, Boyce L, Brennand S, Field JK, Betticher DC, Ratschiller D, Gugger M, Donovan M, Lasek A, Rickert P. Expression profiling of primary non-small cell lung cancer for target identification. Oncogene, 21: 7749–7763, 2002PubMedCrossRefGoogle Scholar
  28. Virtanen C, Ishikawa Y, Honjoh D, Kimura M, Shimane M, Miyoshi T, Nomura H, Jones MH. Integrated classification of lung tumors and cell lines by expression profiling. Proc Natl Acad Sci USA, 99: 12357–12362, 2002PubMedCrossRefGoogle Scholar
  29. Ikehara M, Oshita F, Sekiyama A, Hamanaka N, Saito H, Yamada K, Noda K, Kameda Y, Miyagi Y. Genome-wide cDNA microarray screening to correlate gene expression profile with survival in patients with advanced lung cancer. Oncol Rep, 11: 1041–1044, 2004PubMedGoogle Scholar
  30. Chao YC, Pan SH, Yang SC, Yu SL, Che TF, Lin CW, Tsai MS, Chang GC, Wu CH, Wu YY, Lee YC, Hong TM, Yang PC. Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma. Am J Respir Crit Care Med, 179: 123–133, 2009PubMedCrossRefGoogle Scholar
  31. Shedden K, Taylor JM, Enkemann SA, Tsao MS, Yeatman TJ, Gerald WL, Eschrich S, Jurisica I, Giordano TJ, Misek DE, Chang AC, Zhu CQ, Strumpf D, Hanash S, Shepherd FA, Ding K, Seymour L, Naoki K, Pennell N, Weir B, Verhaak R, Ladd-Acosta C, Golub T, Gruidl M, Sharma A, Szoke J, Zakowski M, Rusch V, Kris M, Viale A, Motoi N, Travis W, Conley B, Seshan VE, Meyerson M, Kuick R, Dobbin KK, Lively T, Jacobson JW, Beer DG. Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med, 14: 822–827, 2008PubMedCrossRefGoogle Scholar
  32. Chen HY, Yu SL, Chen CH, Chang GC, Chen CY, Yuan A, Cheng CL, Wang CH, Terng HJ, Kao SF, Chan WK, Li HN, Liu CC, Singh S, Chen WJ, Chen JJ, Yang PC. A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med, 356: 11–20, 2007PubMedCrossRefGoogle Scholar
  33. 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, 17: 206–218, 2009PubMedCrossRefGoogle Scholar
  34. Girard N, Deshpande C, Lau C, Finley D, Rusch V, Pao W, Travis WD. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol, 33: 1752–1764, 2009PubMedCrossRefGoogle Scholar
  35. Loo PS, Thomas SC, Nicolson MC, Fyfe MN, Kerr KM. Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. J Thorac Oncol, 5: 442–447, 2010PubMedCrossRefGoogle Scholar
  36. Ou SH, Zell JA. Carcinoma NOS is a common histologic diagnosis and is increasing in proportion among non-small cell lung cancer histologies. J Thorac Oncol, 4: 1202–1211, 2009PubMedCrossRefGoogle Scholar
  37. Rivera MP, Mehta AC. Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines, (2nd edn). Chest, 132: 131S–148S, 2007PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  1. 1.Research Unit Molecular Lung and Pleura Pathology, Institute of PathologyMedical University of GrazGrazAustria

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