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Small Cell Carcinoma

  • Elisabeth Brambilla
Part of the Molecular Pathology Library book series (MPLB, volume 1)

Abstract

Small cell carcinoma is defined as a malignant epithelial tumor consisting of small cells with scant cytoplasm, defined cytoplasmic border, typical finely granular “salt and pepper” nuclear chromatin pattern, and inconspicuous or absent nucleoli. Small cell carcinoma is characterized by extensive necrosis, a high mitosis rate, and conspicuous nuclear molding. The criteria of the definition of small cell carcinoma have not changed from the original World Health Organization classification to the revised ones.1,2 The definition is based essentially on cytologic criteria, and the most discriminating criteria probably are the chromatin pattern and the very high nuclear to cytoplasmic ratio (8 to 9/10) beyond cell size. Fortunately, the definition of small cell lung carcinoma (SCLC) did not change so that the literature on clinical behavior, molecular biology, molecular pathology, and drug sensitivity are still relevant. The only major change between the recent and previous classifications resides in the abandonment of the variant intermediate cell type of oat cell carcinoma, essentially because of a lack of clinical and therapeutic differences.

Keywords

Vascular Endothelial Growth Factor Small Cell Lung Cancer Small Cell Carcinoma Small Cell Lung Carcinoma Small Cell Lung Cancer Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Travis WD, Colby TV, Corrin B, et al. WHO Histological Classification of Tumours. Histological Typing of Lung and Pleural Tumours, 3rd ed. Berlin: Springer-Verlag; 1999.Google Scholar
  2. 2.
    Travis WD, Brambilla E, Muller-Hemerlink HK, Harris CC, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004.Google Scholar
  3. 3.
    Nicholson SA, Beasley MB, Brambilla E, et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 2002;26:1184–1197.CrossRefPubMedGoogle Scholar
  4. 4.
    Lantuejoul S, Moro D, Michalides RJ, et al. Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors. Am J Surg Pathol 1998;22:1267–1276.CrossRefPubMedGoogle Scholar
  5. 5.
    Sturm N, Rossi G, Lantuejoul S, et al. Expression of thyroid transcription factor-1 (TTF-1) in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids. Hum Pathol 2002;33(2):175–182.CrossRefPubMedGoogle Scholar
  6. 6.
    Halliday BE, Slagel DD, Elsheikh TE, et al. Diagnostic utility of MIC-2 immunocytochemical staining in the differential diagnosis of small blue cell tumors. Diagn Cytopathol 1998;19:410–416.CrossRefPubMedGoogle Scholar
  7. 7.
    Lumadue JA, Askin FB, Perlman EJ. MIC2 analysis of small cell carcinoma. Am J Clin Pathol 1994;102:692–694.PubMedGoogle Scholar
  8. 8.
    Pelosi G, Leon ME, Veronesi G, et al. Decreased immunoreactivity of CD99 is an independent predictor of regional lymph node metastases in pulmonary carcinoid tumors. J Thorac Oncol 2006;1(5):468–477.CrossRefPubMedGoogle Scholar
  9. 9.
    Balsara BR, Testa JR. Chromosomal imbalances in human lung cancer. Oncogene 2002;21:6877–6883.CrossRefPubMedGoogle Scholar
  10. 10.
    Petersen I, Langreck H, Wolf G, et al. Small-cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17. Br J Cancer 1997;75(1):79–86.PubMedGoogle Scholar
  11. 11.
    Petersen I, Hidalgo A, Petersen S, et al. Chromosomal imbalances in brain metastases of solid tumors. Brain Pathol 2000;10:395–401.PubMedCrossRefGoogle Scholar
  12. 12.
    Watkins DN, Berman DM, Burkholder SG, et al. Hedgehog signaling within airway epithelial progenitors and in small cell lung cancer. Nature 2003;422:313–317.CrossRefPubMedGoogle Scholar
  13. 13.
    Borges M, Linnoila RI, van de Velde HJ, et al. An achaetescute homologue essential for neuroendocrine differentiation in the lung. Nature 1997;386:852–855.CrossRefPubMedGoogle Scholar
  14. 14.
    Ito T, Udaka N, Yazawa T, et al. Basic helix-loop-helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium. Development 2000;127:3913–3921.PubMedGoogle Scholar
  15. 15.
    Linnoila RI, Zhao B, DeMayo JL, et al. Constitutive achaetescute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. Cancer Res 2000;60:4005–4009.PubMedGoogle Scholar
  16. 16.
    Jiang SX, Kameya T, Asamura H, et al. hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors. Mod Pathol 2004;17:222–229.CrossRefPubMedGoogle Scholar
  17. 17.
    Gazzeri S, Brambilla E, Caron De Fromentel C, et al. p53 genetic abnormalities and myc activation in human lung carcinomas. Int J Cancer 1994;58:24–32.CrossRefPubMedGoogle Scholar
  18. 18.
    Brambilla E, Negoescu A, Gazzeri S, et al. Apoptosis-related factors P53, Bcl2, and Bax in neuroendocrine lung tumors. Am J Pathol 1996;149:1941–1952.PubMedGoogle Scholar
  19. 19.
    Jiang SX, Kameya T, Sato Y, et al. Bcl2 protein expression in lung cancer and close correlation with neuroendocrine differentiation. Am J Pathol 1996;148:837–846.PubMedGoogle Scholar
  20. 20.
    Gastman BR, Atarshi Y, Reichert TE, et al. Fas ligand is expressed on human squamous cell carcinomas of the head and neck, and it promotes apoptosis of T lymphocytes. Cancer Res 1999;59:5356–5364.PubMedGoogle Scholar
  21. 21.
    Ungefroren H, Voss M, Jansen M, et al. Human pancreatic adenocarcinomas express Fas and Fas ligand yet are resistant to Fas-mediated apoptosis. Cancer Res 1998;58:1741–1749.PubMedGoogle Scholar
  22. 22.
    Viard-Leveugle I, Veyrenc S, French LE, et al. Frequent loss of Fas expression and function in human lung tumors with overexpression of FasL in small cell lung carcinoma. J Pathol 2003;(201)2:268–277.CrossRefGoogle Scholar
  23. 23.
    Shivapurkar N, Toyooka S, Eby MT, et al. Differential inactivation of caspase-8 in lung cancer. Cancer Biol Ther 2002;1(1):54–58.Google Scholar
  24. 24.
    Holler N, Zaru R, Micheau O, et al. Fas triggers an alternative caspase 8-independent cell death pathway using kinase RIP as effector molecule. Nat Immunol 2000;1:489–495.CrossRefPubMedGoogle Scholar
  25. 25.
    Cagle PT, El-Naggar AK, Xu HJ, et al. Differential retinoblastoma protein expression in neuroendocrine tumors of the lung. Am J Pathol 1997;150:393–400.PubMedGoogle Scholar
  26. 26.
    Gouyer V, Gazzeri S, Bolon I, et al. Mechanism of retinoblastoma gene inactivation in the spectrum of neuroendocrine lung tumors. Am J Respir Cell Mol Biol 1998;18:188–196.PubMedGoogle Scholar
  27. 27.
    Yuan J, Knorr J, Altmannsberger M, et al. Expression of p16 and lack of pRB in primary small cell lung cancer. J Pathol 1999;189:358–362.CrossRefPubMedGoogle Scholar
  28. 28.
    Harbour JW, Lai SL, Whang-Peng J, et al. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 1988;241:353–357.CrossRefPubMedGoogle Scholar
  29. 29.
    Dosaka-Akita H, Cagle PT, Hiroumi H, et al. Differential retinoblastoma and p16(INK4) protein expression in neuroendocrine tumors of the lung. Cancer 2000;88:550–556.CrossRefPubMedGoogle Scholar
  30. 30.
    Kratzke RA, Greatens TM, Rubins JB, et al. Rb and p16INK4 expression in resected non small cell lung tumors. Cancer Res 1996;56:3415–3420.PubMedGoogle Scholar
  31. 31.
    Gazzeri S, Gouyer V, Vour’ch C, et al. Mechanism of p16INK4A inactivation in non small-cell lung cancers. Oncogene 1998;16(4):497–505.CrossRefPubMedGoogle Scholar
  32. 32.
    Beasley MB, Lantuejoul S, Abbondanzo S, et al. The p16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung. Hum Pathol 2003;34(2):136–142.CrossRefPubMedGoogle Scholar
  33. 33.
    Sherr CJ. Tumour surveillance via the ARF-p53 pathway. Genes Dev 1998;12:2984–2991.CrossRefPubMedGoogle Scholar
  34. 34.
    Eymin B, Leduc C, Coll JL, et al. P14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumors established in nude mice. Oncogene 2003;22:1822–1835.CrossRefPubMedGoogle Scholar
  35. 35.
    Hemmati PG, Gillissen B, von Haefen C, et al. Adenovirus-mediated overexpression of p14(ARF) induces p53 and Bax-independent apoptosis. Oncogene 2002;21:3149–3161.CrossRefPubMedGoogle Scholar
  36. 36.
    Weber JD, Jeffers JR, Rehg JE, et al. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev 2000;14:2358–2365.CrossRefPubMedGoogle Scholar
  37. 37.
    Eymin B, Claverie P, Salon C, et al. p14ARF activates a Tip60-dependent ATM/ATR/CHK pathway in response to genotoxic stresses. Mol Cell Biol 2006;26(11):4339–4350.CrossRefPubMedGoogle Scholar
  38. 38.
    Gazzeri S, Della Valle V, Chaussade L, et al. The human p19ARF protein encoded by the β transcript of the p16INK4 gene is frequently lost in small cell lung tumors. Cancer Res 1998;58:3926–3931.PubMedGoogle Scholar
  39. 39.
    Eymin B, Claverie P, Salon C, et al. P14ARF triggers G2 arrest through ERK-mediated Cdc25C phosphorylation, ubiquitination and proteasomal degradation. Cell Cycle 2006;5(7):759–765.PubMedGoogle Scholar
  40. 40.
    Chen J, Marechal V, Levine AJ. Mapping of the p53 and mdm-2 interaction domains. Mol Cell Biol 1993;13:4107–4114.PubMedGoogle Scholar
  41. 41.
    Momand J, Zambetti GP, Olson DC, et al. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992;69:1237–1245.CrossRefPubMedGoogle Scholar
  42. 42.
    Oliner JD, Pietenpol JA, Thiagalingam S, et al. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature 1993;362:857–860.CrossRefPubMedGoogle Scholar
  43. 43.
    Haupt Y, Maya R, Kazaz A, et al. Mdm2 promotes the rapid degradation of p53. Nature 1997;387:296–299.CrossRefPubMedGoogle Scholar
  44. 44.
    Tao W, Levine AJ. Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. Proc. Natl Acad Sci USA 1999;96:3077–3080.CrossRefGoogle Scholar
  45. 45.
    Weber JD, Taylor LJ, Roussel MF, et al. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1999;1:20–26.CrossRefPubMedGoogle Scholar
  46. 46.
    Cordon-Cardo C, Latres E, Drobnjak M, et al. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res 1994;54:794–799.PubMedGoogle Scholar
  47. 47.
    Eymin B, Gazzeri S, Brambilla C, et al. Distinct pattern of E2F1 expression in human lung tumors: E2F1 is upregulated in small cell lung carcinoma. Oncogene 2001;20:1678–1687.CrossRefPubMedGoogle Scholar
  48. 48.
    Zabarovsky ER, Lerman MI, Minna JD. Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 2002;21:6915–6935.CrossRefPubMedGoogle Scholar
  49. 49.
    Sozzi G, Pastorino U, Moiraghi L, et al. Loss of FHIT function in lung cancer and preinvasive bronchial lesions. Cancer Res 1998;58:5032–5037.PubMedGoogle Scholar
  50. 50.
    Sard L, Accornero P, Tornielli S, et al. The tumor suppressor gene FHIT is involved in the regulation of apoptosis and cell cycle control. Proc Natl Acad Sci USA 1999;96:8489–8492.CrossRefPubMedGoogle Scholar
  51. 51.
    Dammann R, Li C, Yoon JH, et al. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. 52. Nat Genet 2000;25:315–319.CrossRefPubMedGoogle Scholar
  52. 52.
    Burbee DG, Forgacs E, Zochbauer-Muller S, et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001;93:691–699.CrossRefPubMedGoogle Scholar
  53. 53.
    Virmani AK, Rathi A, Zöchbauer-Müller S, et al. Promoter methylation and silencing of the retinoic acid receptor-β gene in lung carcinomas. J Natl Cancer Inst 2000;92:1303–1307.CrossRefPubMedGoogle Scholar
  54. 54.
    Holt SE, Shay JW. Role of telomerase in cellular proliferation and cancer. J Cell Physiol 1999;180:10–18.CrossRefPubMedGoogle Scholar
  55. 55.
    Lantuejoul S, Soria JC, Lorimier P, et al. Differential expression of telomerase reverse transcriptase (hTERT) in lung tumors. Br J Cancer 2004;90:1222–1229.CrossRefPubMedGoogle Scholar
  56. 56.
    Hiyama K, Hiyama E, Ishioka S, et al. Telomerase activity in small cell and non small cell lung cancers. J Natl Cancer Inst 1995;87:895–902.CrossRefPubMedGoogle Scholar
  57. 57.
    Albanell J, Lonardo F, Rush V, et al. High telomerase activity in primary lung cancers: association with increased cell proliferation rates and advanced pathologic stage. J Natl Cancer Inst 1997;89:1609–1615.CrossRefPubMedGoogle Scholar
  58. 58.
    Gomez-Roman JJ, Fontalba Romero A, Sanchez Castro L, et al. Telomerase activity in pulmonary neuroendocrine tumours. Am J Surg Pathol 2000;24:417–421.CrossRefPubMedGoogle Scholar
  59. 59.
    Lantuejoul S, Salon C, Soria JC, et al. Telomerase expression in lung preneoplasia and neoplasia. Int J Cancer 2007;120:1835–1841.CrossRefPubMedGoogle Scholar
  60. 60.
    Decaussin M, Sartelet H, Robert C, et al. Expression of vascular endothelial growth factor (VEGF) and its receptors (VEGF-R1-Flt1 and VEGF-R2-Flk1/KDR) in non small cell lung carcinoma (NSCLC): correlation with angiogenesis and survival. J. Pathol 1999;188:369–377.CrossRefGoogle Scholar
  61. 61.
    Tian X, Song S, Wu J, et al. Vascular endothelial growth factor: acting as an autocrine growth factor for human gastric adenocarcinoma cell MGC803. Biochem Biophys Res Commun 2001;286:505–512.CrossRefPubMedGoogle Scholar
  62. 62.
    Lantuejoul S, Constantin B, Drabkin H, et al. Expression of VEGF, semaphorin SEMA3F and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumors and cell lines. J Pathol 2003;200:336–347.CrossRefPubMedGoogle Scholar
  63. 63.
    Compernolle V, Brusselmans K, Acker T, et al. Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nature Med 2 2002;(8)7:702–710.Google Scholar
  64. 64.
    Kusy S, Nasarre P, Chan D, et al. Selective suppression of in vivo tumorigenicity by semaphoring SEMA3F in lung cancer cells. Neoplasia 2005;7(5):457–465.CrossRefPubMedGoogle Scholar
  65. 65.
    Salon C, Moro D, Lantuejoul S, et al. The E-cadherin/β-catenin adhesion complex in neuroendocrine tumors of the lung: a suggested role upon local invasion and metastasis. Hum Pathol 2004;35(9):1148–1155.CrossRefPubMedGoogle Scholar
  66. 66.
    Salon C, Lantuejoul S, Eymin B, et al. The E-cadherin-β-catenin complex and its implication in lung cancer progression and prognosis. Future Oncol 2005;1(5):649–660.CrossRefPubMedGoogle Scholar
  67. 67.
    Clavel CE, Nollet F, Berx G, et al. Expression of the Ecadherin-catenin complex in lung neuroendocrine tumours. J Pathol 2001;194:20–26.CrossRefPubMedGoogle Scholar
  68. 68.
    Heldin CH, Ostman A, Ronnstrand L. Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1998;1378:F79–F113.PubMedGoogle Scholar
  69. 69.
    Pelosi G, Fasullo M, Leon ME, et al. CD117 immunoreactivity in high-grade neuroendocrine tumors of the lung: a comparative study of 39 large-cell neuroendocrine carcinomas and 27 surgically resected small-cell carcinomas. Virchows Arch 2004;445:449–455.CrossRefPubMedGoogle Scholar
  70. 70.
    Rossi G, Cavazza A, Marchioni A, et al. Kit expression in small cell carcinomas of the lung: effects of chemotherapy. Mod Pathol 2003;16:1041–1047.CrossRefPubMedGoogle Scholar
  71. 71.
    Hibi K, Takahashi T, Sekido Y, et al. Coexpression of stem cell factor and the c-kit genes in small-cell lung cancer. Oncogene 1991;6:2291–2296.PubMedGoogle Scholar
  72. 72.
    Rygaard K, Nakamura T, Spang-Thomsen M. Expression of the protooncogene c-met and c-kit and their ligands, hepatocyte growth factor/scatter factor and stem cell factor in SCLC cell lines and xenografts. Br J Cancer 1993;67:137–146.Google Scholar
  73. 73.
    Krystal GW, Hines SJ, Organ CP. Autocrine growth of small cell lung cancer mediated by coexpression of c-kit and stem cell factor. Cancer Res 1996;56:370–376.PubMedGoogle Scholar
  74. 74.
    Tamborini E, Bonadiman L, Negri T, et al. Detection of overexpression and phosphorylation wild-type Kit receptor in surgical specimens of small cell lung cancer. Clin Cancer Res 2004;10:8214–8219.CrossRefPubMedGoogle Scholar
  75. 75.
    Maulik G, Shrikhande A, Kijima T, et al. Role of the hepatocyte growth factor receptor, c-Met, in the oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev 2002;13:41–59.CrossRefPubMedGoogle Scholar
  76. 76.
    Ma PC, Maulik G, Christensen J, et al. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 2003;22:309–325.CrossRefPubMedGoogle Scholar
  77. 77.
    Trusolino L, Comoglio PM. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nature Rev 2002;2:289–300.CrossRefGoogle Scholar
  78. 78.
    Maulik G, Kijima T, Ma PC, et al. Modulation of the c-met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res 2002;8:620–627.PubMedGoogle Scholar
  79. 79.
    Ma PC, Kijima T, Maulik G, et al. C-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res 2003;63:6272–6281.PubMedGoogle Scholar
  80. 80.
    Wang WL, Healy ME, Sattler M, et al. Growth inhibition and modulation of kinase pathways on small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI571. Oncogene 2000;19:3521–3528.CrossRefPubMedGoogle Scholar
  81. 81.
    Krystal GW, Honsawek S, Litz J, et al. The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. Clin Cancer Res 2000;6:3319–3326.PubMedGoogle Scholar
  82. 82.
    Krystal GW, Honsawek S, Kiewlich D, et al. Indolinone tyrosine kinase inhibitors block Kit activation and growth of small cell lung cancer cells. Cancer Res 2001;61:3660–68.PubMedGoogle Scholar
  83. 83.
    Abrams TJ, Lee LB, Murray LJ, et al. SU11248 inhibits KIT and platelet-derived growth factor receptor β in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003;2:471–478.PubMedGoogle Scholar
  84. 84.
    Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000;295:139–145.PubMedGoogle Scholar
  85. 85.
    Bondzi C, Litz J, Dent P, et al. Src family kinase activity is required for Kit-mediated mitogen-activated protein (MAP) kinase activation; however, loss of functional retinoblastoma protein makes MAP kinase activation unnecessary for growth of small cell lung cancer cells. Cell Growth Differ 2000;11:305–314.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Elisabeth Brambilla
    • 1
  1. 1.Department of Pathology, CHU de Grenoble Albert Michallon, Lung Cancer Research GroupINSERM U578GrenobleFrance

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