Molecular Pathology of Precursor and Pre-invasive Lesions

Chapter
Part of the Molecular Pathology Library book series (MPLB, volume 6)

Abstract

This chapter discusses the molecular biology of pulmonary pre-invasive lesions. Most is known about the changes found in squamous dysplasia/carcinoma in situ of the bronchial epithelium. Many of these molecular changes are probably induced by tobacco carcinogens. The loss of tumour suppressor gene (TSG) function is probably more important than oncogene activation in promoting consequent growth activation. Loss of TSG function may be due to mutation, deletion, epigenetic silencing or activation of inhibitory mechanisms. Important TSGs include P53, P16 and others on chromosome 3. There is also molecular evidence, in squamous dysplasia and squamous carcinoma in situ (SD/CIS), of significant alterations in the other factors considered the Hallmarks of Cancer, namely evasion of apoptosis, limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis. Rather less is known about the molecular changes found in atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) although the same five characteristics of malignant change all show, to a varying degree, alteration in molecular pathways relevant to each. In this pathway of carcinogenesis, oncogene activation, leading to growth promotion has a greater importance with epidermal growth factor receptor or KRAS mutation potentially important. Many of the same mechanisms of TSG inactivation seen in SD/CIS appear active in at least some cases of AAH or AIS. Virtually nothing is known about the molecular biology of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

Keywords

Surfactant Tyrosine Adenocarcinoma Smoke Androgen 

References

  1. 1.
    Franklin WA, Wistuba II, Geisinger KR, et al. Squamous dysplasia and carcinoma in situ. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al., editors. World Health Organisation classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004. p. 68–72.Google Scholar
  2. 2.
    Kerr KM, Fraire AE, Pugatch B, et al. Atypical adenomatous hyperplasia. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al., editors. World Health Organisation classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004. p. 73–5.Google Scholar
  3. 3.
    Travis WD, Gosney JG. Diffuse pulmonary neuroendocrine cell hyperplasia. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al., editors. World Health Organisation classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004. p. 76–8.Google Scholar
  4. 4.
    Mao L. Molecular abnormalities in lung carcinogenesis and their potential clinical implications. Lung Cancer. 2001;34:S27–34.PubMedCrossRefGoogle Scholar
  5. 5.
    Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res. 2003;63:1727–30.PubMedGoogle Scholar
  6. 6.
    Park IW, Wistuba II, Maitra A, et al. Multiple clonal abnormalities in the bronchial epithelium of patients with lung cancer. J Natl Cancer Inst. 1999;91: 1863–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Kotton DN, Fine A. Lung stem cells. Cell Tissue Res. 2008;331:145–56.PubMedCrossRefGoogle Scholar
  8. 8.
    Wistuba II, Behrens C, Milchgrub S, et al. Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinomas. Oncogene. 1999;18:643–50.PubMedCrossRefGoogle Scholar
  9. 9.
    Wistuba II, Mao L, Gazdar AF. Smoking molecular damage in bronchial epithelium. Oncogene. 2002;21:7298–306.PubMedCrossRefGoogle Scholar
  10. 10.
    Ma J, Gao M, Lu Y, et al. Gain of 1q25-32, 12q23-24.3, and 17q12-22 facilitates tumourigenesis and progression of human squamous cell lung cancer. J Pathol. 2006;210:205–13.PubMedCrossRefGoogle Scholar
  11. 11.
    Woenckhaus M, Klein-Hitpass L, Grepmeier U, Merk J, Pfeifer M, Wild P, et al. Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell-lung cancers. J Pathol. 2006;210:192–204.PubMedCrossRefGoogle Scholar
  12. 12.
    Wistuba II, Behrens C, Virmani AK, et al. Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer. Cancer Res. 1999;59:1973–9.PubMedGoogle Scholar
  13. 13.
    Schatzkin A. Sir Richard Doll on chance and genetic susceptibility in carcinogenesis, or, why not all smokers get lung cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:1420.PubMedCrossRefGoogle Scholar
  14. 14.
    Doll R. Commentary: the age distribution of cancer and a multistage theory of carcinogenesis. Int J Epidemiol. 2004;33:1183–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Hirano T, Franzen B, Kato H, et al. Genesis of squamous cell lung carcinoma. Sequential changes of proliferation, DNA ploidy and p53 expression. Am J Pathol. 1994;144:296–302.PubMedGoogle Scholar
  17. 17.
    Pendelton N, Dixon GR, Burnett HE, et al. Expression of proliferating cell nuclear antigen (PCNA) in dysplasia of the bronchial epithelium. J Pathol. 1993;170:169–72.CrossRefGoogle Scholar
  18. 18.
    Schlake G, Muller KM. Carcinogenesis in bronchial epithelium—an immunohistochemical evaluation of preneoplastic lesions. Virchows Arch. 2003; 443:291.Google Scholar
  19. 19.
    Meert AP, Martin B, Verdebout JM, et al. EGFR, c-erbB-2 and ki-67 in NSCLC and preneoplastic bronchial lesions. Anticancer Res. 2006;26:135–8.PubMedGoogle Scholar
  20. 20.
    Tan D-F, Huberman JA, Hyland A, et al. MCM2—a promising marker for premalignant lesions of the lung: a cohort study. BMC Cancer. 2001;1:6–14.PubMedCrossRefGoogle Scholar
  21. 21.
    Khuri FR, Lee JS, Lippman SM, et al. Modulation of proliferating cell nuclear antigen in the bronchial epithelium of smokers. Cancer Epidemiol Biomarkers Prev. 2001;10:311–8.PubMedGoogle Scholar
  22. 22.
    Lee JJ, Liu D, Lee JS, et al. Long-term impact of smoking on lung epithelial proliferation in current and former smokers. J Natl Cancer Inst. 2001;93: 1081–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Rusch V, Klimstra D, Linkov I, et al. Aberrant expression of p53 or the epidermal growth factor receptor is frequent in early bronchial neoplasia and coexpression precedes squamous cell carcinoma development. Cancer Res. 1995;55:1365–72.PubMedGoogle Scholar
  24. 24.
    Piyathilake CJ, Frost AR, Manne U, et al. Differential expression of growth factors in squamous cell carcinoma and precancerous lesions of the lung. Clin Cancer Res. 2002;8:734–44.PubMedGoogle Scholar
  25. 25.
    Franklin WA, Veve R, Hirsch FR, et al. Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol. 2002;29:3–14.PubMedCrossRefGoogle Scholar
  26. 26.
    Meert AP, Martin B, Verdebout JM, et al. Does c-erbB-2 play a role in the first steps of lung carcinogenesis? Anticancer Res. 2005;25:2005–8.PubMedGoogle Scholar
  27. 27.
    Merrick DT, Kittelson J, Winterhalder R, et al. Analysis of c-ErbB1/epidermal growth factor receptor and c-ErbB2/HER-2 expression in bronchial dysplasia: evaluation of potential targets for chemoprevention of lung cancer. Clin Cancer Res. 2006;12:2281–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Sugio K, Kishimoto Y, Virmani AK, et al. K-ras mutations are a relatively late event in the pathogenesis of lung carcinomas. Cancer Res. 1994;54: 5811–6.PubMedGoogle Scholar
  29. 29.
    Sos ML, Fischer S, Ullrich R, et al. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci U S A. 2009;106:18351–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Tsao AS, McDonnell T, Lam S, et al. Increased phospho-AKT (Ser473) expression in bronchial dysplasia: implications for lung cancer prevention studies. Cancer Epidemiol Biomarkers Prev. 2003;12:660–4.PubMedGoogle Scholar
  31. 31.
    Massion PP, Taflan PM, Shyr Y, et al. Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Am J Respir Crit Care Med. 2004;170:1088–94.PubMedCrossRefGoogle Scholar
  32. 32.
    Sato M, Shames DS, Gazdar AF, et al. A translational view of the molecular pathology of lung cancer. J Thorac Oncol. 2007;2:327–43.PubMedCrossRefGoogle Scholar
  33. 33.
    Lantuejoul S, Salameire D, Salon D, et al. Pulmonary premeoplasia—sequential molecular carcinogenetic events. Histopathology. 2009;54:43–54.PubMedCrossRefGoogle Scholar
  34. 34.
    Sozzi G, Miozzo M, Donghi R, et al. Deletions of 17p and p53 mutations in preneoplastic lesions of the lung. Cancer Res. 1992;52:6079–82.PubMedGoogle Scholar
  35. 35.
    Sundaresan V, Ganly P, Hasleton PS, et al. P53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene. 1992;7:1989–97.PubMedGoogle Scholar
  36. 36.
    Nuorva K, Soini Y, Kamel D, et al. Concurrent p53 expression in bronchial dysplasias and squamous cell lung carcinomas. Am J Pathol. 1993;142:725–32.PubMedGoogle Scholar
  37. 37.
    Bennett WP, Colby TV, Travis WD, et al. p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res. 1993;53:4817–22.PubMedGoogle Scholar
  38. 38.
    Walker C, Robertson LJ, Myskow MW, et al. P53 expression in normal and dysplastic bronchial epithelium and in lung carcinomas. Br J Cancer. 1994;70:297–303.PubMedCrossRefGoogle Scholar
  39. 39.
    Fontanini G, Vignati S, Bigini D, et al. Human non-small cell lung cancer: p53 protein accumulation is an early event and persists during metastatic progression. J Pathol. 1994;174:23–31.PubMedCrossRefGoogle Scholar
  40. 40.
    Katabami M, Dosaka-Akita H, Honma K, et al. P53 and bcl-2 expression in pneumoconiosis-related pre-cancerous lesions and lung cancers: frequent and preferential p53 expression in pneumoconiotic bronchiolar dysplasias. Int J Cancer. 1998;75:504–11.PubMedCrossRefGoogle Scholar
  41. 41.
    Brambilla E, Gazzeri S, Lantuejoul S, et al. P53 mutant immunophenotype and deregulation of p53 transcription pathway (bcl2, bax and waf1) in precursor bronchial lesions of lung cancer. Clin Cancer Res. 1998;4:1609–18.PubMedGoogle Scholar
  42. 42.
    Lonardo F, Rusch V, Langenfeld J, et al. Overexpression of cyclins D1 and E is frequent in bronchial preneoplasia and precedes squamous cell carcinoma development. Cancer Res. 1999;59:2470–6.PubMedGoogle Scholar
  43. 43.
    Martin B, Verdebout J-M, Mascaux C, et al. Expression of p53 in preneoplastic and early neoplastic bronchial lesions. Oncol Rep. 2002;9:223–9.PubMedGoogle Scholar
  44. 44.
    Vahakangas KH, Samet JM, Metcalf RA, et al. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet. 1992;339: 576–80.PubMedCrossRefGoogle Scholar
  45. 45.
    Kohno H, Hiroshima K, Toyozaki T, et al. p53 mutation and allelic loss of chromosome 3p, 9p of preneoplastic lesions in patients with non-small cell lung carcinoma. Cancer. 1999;85:341–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Franklin WA, Gazdar AF, Haney J, et al. Widely ­dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. J Clin Invest. 1997;100:2133–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Massion PP, Taflan PM, Jamshedur Rahman SM, et al. Significance of p63 amplification and overexpression in lung cancer development and prognosis. Cancer Res. 2003;63:7113–21.PubMedGoogle Scholar
  48. 48.
    Mascaux C, Bex F, Martin B, et al. The role of NPM, p14arf and MDM2 in precursors of bronchial squamous cell carcinoma. Eur Respir J. 2008;32: 678–86.PubMedCrossRefGoogle Scholar
  49. 49.
    Lamy A, Sesboue R, Bourguignon J, et al. Aberrant methylation of the CDKN2A/P16INK4A gene promoter region in preinvasive bronchial lesions: a prospective study in high-risk patients without invasive cancer. Int J Cancer. 2002;100:189–93.PubMedCrossRefGoogle Scholar
  50. 50.
    Breuer RHJ, Snijders PJF, Sutedja GT, et al. expression of the P16 INK4a gene product, methylation of the p16 INK4a promoter region and expression of the polycomb-group gene BMI-1 in squamous cell carcinoma and premalignant endobronchial lesions. Lung Cancer. 2005;48:299–306.PubMedCrossRefGoogle Scholar
  51. 51.
    Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci U S A. 1998;95:11891–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Brambilla E, Gazzeri S, Moro D, et al. Alterations of Rb pathway (Rb-p16INK4-cyclin D1) in preinvasive bronchial lesions. Clin Cancer Res. 1999;5:243–50.PubMedGoogle Scholar
  53. 53.
    Toyooka S, Maruyama R, Toyooka KO, et al. Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. Int J Cancer. 2003;103:153–60.PubMedCrossRefGoogle Scholar
  54. 54.
    Thiberville L, Payne P, Vielkinds J, et al. Evidence of cumulative gene losses with progression of premalignant epithelial lesions to carcinoma of the bronchus. Cancer Res. 1995;55:5133–9.PubMedGoogle Scholar
  55. 55.
    Kishimoto Y, Sugio K, Hung JY, et al. Allele-specific loss in chromosome 9p loci in preneoplastic lesions accompanying non-small-cell lung cancers. J Natl Cancer Inst. 1995;87:1224–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Boyle JO, Lonardo F, Chang JH, et al. Multiple high-grade bronchial dysplasia and squamous cell carcinoma: concordant and discordant mutations. Clin Cancer Res. 2001;7:259–66.PubMedGoogle Scholar
  57. 57.
    Martinet N, Alla F, Farre G, et al. Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions. Cancer Res. 2000;60:2869–75.PubMedGoogle Scholar
  58. 58.
    Sozzi G, Tornielli S, Tagliabue E, et al. Absence of Fhit protein in primary lung tumors and cell lines with FHIT gene abnormalities. Cancer Res. 1997;57: 5207–12.PubMedGoogle Scholar
  59. 59.
    Sozzi G, Pastorino U, Moiraghi L, et al. Loss of FHIT function in lung cancer and preinvasive bronchial lesions. Cancer Res. 1998;58:5032–7.PubMedGoogle Scholar
  60. 60.
    Tormanen U, Nuorva K, Soini Y, et al. Apoptotic activity is increased in parallel with the metaplasia-dysplasia-carcinoma sequence of the bronchial epithelium. Br J Cancer. 1999;79:996–1002.PubMedCrossRefGoogle Scholar
  61. 61.
    Yashima K, Litzky LA, Kaiser L, et al. Telomerase expression in respiratory epithelium during the multistage pathogenesis of lung carcinomas. Cancer Res. 1997;57:2373–7.PubMedGoogle Scholar
  62. 62.
    Capkova L, Kalinova M, Krskova L, et al. Loss of heterozygosity and human telomerase reverse transcription (hTERT) expression in bronchial mucosa of heavy smokers. Cancer. 2007;109:2299–307.PubMedCrossRefGoogle Scholar
  63. 63.
    Shibuya K, Fujisawa T, Hoshino H, et al. Increased telomerase activity and elevated hTERT mRNA expression during multistage carcinogenesis of squamous cell carcinoma of the lung. Cancer. 2001;92:849–55.PubMedCrossRefGoogle Scholar
  64. 64.
    Snijders PJ, Breuer RH, Sutedja GT, et al. Elevated hTERT mRNA levels: a potential determinant of bronchial squamous cell carcinoma (in situ). Int J Cancer. 2004;109:412–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Gazdar AF, Minna JD. Angiogenesis and the multistage development of lung cancers. Clin Cancer Res. 2000;6:1611–2.PubMedGoogle Scholar
  66. 66.
    Fisseler-Eckhoff A, Rothstein D, Muller KM. Neovascularisation in hyperplastic, metaplastic and potentially preneoplastic lesions of the bronchial mucosa. Virchows Arch. 1996;429:95–100.PubMedCrossRefGoogle Scholar
  67. 67.
    Fontanini G, Calcinai A, Boldrini L, et al. Modulation of neoangiogenesis in bronchial preneoplastic lesions. Oncol Rep. 1999;6:813–7.PubMedGoogle Scholar
  68. 68.
    Meert A-P, Feoli F, Martin B, et al. Angiogenesis in preinvasive, early invasive bronchial lesions and micropapillomatosis and correlation with EGFR expression. Histopathology. 2007;50:311–7.PubMedCrossRefGoogle Scholar
  69. 69.
    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 tumours, and cell lines. J Pathol. 2003;200:336–47.PubMedCrossRefGoogle Scholar
  70. 70.
    Merrick DT, Haney J, Petrunich S, et al. Overexpression of vascular endothelial growth factor and its receptors in bronchial dysplasia demonstrated by quantitative RT-PCR analysis. Lung Cancer. 2005;48:31–45.PubMedCrossRefGoogle Scholar
  71. 71.
    Mascaux C, Martin B, Verdebout JM, et al. COX-2 expression during early lung squamous cell carcinoma oncogenesis. Eur Respir J. 2005;26:198–203.PubMedCrossRefGoogle Scholar
  72. 72.
    Galateau-Salle FB, Luna RE, Horiba K, et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in bronchial squamous preinvasive lesions. Hum Pathol. 2000;31:296–305.PubMedCrossRefGoogle Scholar
  73. 73.
    Bolon I, Brambilla E, Vandenbunder B, et al. Changes in the expression of matrix proteases and of the transcription factor c-Ets-1 during progression of precancerous bronchial lesions. Lab Invest. 1996;75: 1–13.PubMedGoogle Scholar
  74. 74.
    Kato Y, Hirano T, Yoshida K, et al. Frequent loss of E-cadherin and/or catenins in intrabronchial lesions during carcinogenesis of the bronchial epithelium. Lung Cancer. 2005;48:323–30.PubMedCrossRefGoogle Scholar
  75. 75.
    Sin DD, Man SF, McWilliams A, Lam S. Surfactant protein D and bronchial dysplasia in smokers at high risk of lung cancer. Chest. 2008;134:582–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Boers JE, ten Velde GP, Thunnissen FB. P53 in squamous metaplasia: a marker for risk of respiratory tract carcinoma. Am J Respir Crit Care Med. 1996;153:411–6.PubMedGoogle Scholar
  77. 77.
    Ponticiello A, Barra E, Giani U, et al. P53 immunohistochemistry can identify bronchial dysplastic lesions proceeding to lung cancer: a prospective study. Eur Respir J. 2000;15:547–52.PubMedCrossRefGoogle Scholar
  78. 78.
    Jeanmart M, Lantuejoul S, Fievet F, et al. Value of immunohistochemical markers in preinvasive bronchial lesions in risk assessment of lung cancer. Clin Cancer Res. 2003;9:2195–203.PubMedGoogle Scholar
  79. 79.
    Ocejo-Garcia M, Baokbah TA, Ashurst HL, et al. Roles for USF-2 in lung cancer proliferation and bronchial carcinogenesis. J Pathol. 2005;206: 151–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Tang X, Liu D, Shishodia S, et al. Nuclear factor-kappaB (NF-kappaB) is frequently expressed in lung cancer and preneoplastic lesions. Cancer. 2006;107:2637–46.PubMedCrossRefGoogle Scholar
  81. 81.
    Cappello F, Di Stefano A, David S, et al. Hsp60 and Hsp10 down-regulation predicts bronchial epithelial carcinogenesis in smokers with chronic obstructive pulmonary disease. Cancer. 2006;107:2417–24.PubMedCrossRefGoogle Scholar
  82. 82.
    Snead DR, Perunovic B, Cullen N, et al. hnRNP1 B1 expression in benign and malignant lung disease. J Pathol. 2003;200:88–94.PubMedCrossRefGoogle Scholar
  83. 83.
    Smith SL, Watson SG, Ratschiller D, et al. Maspin—the most commonly-expressed gene of the 18q21.3 serpin cluster in lung cancer—is strongly expressed in preneoplastic bronchial lesions. Oncogene. 2003;22:8677–87.PubMedCrossRefGoogle Scholar
  84. 84.
    Smith AL, Hung J, Walker L, et al. Extensive areas of aneuploidy are present in the respiratory epithelium of lung cancer patients. Br J Cancer. 1996;73: 203–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Romeo MS, Sokolova IA, Morrison LE, et al. Chromosomal abnormalities in non-small cell lung carcinomas and in bronchial epithelia of high-risk smokers detected by multi-target interphase fluorescence in situ hybridization. J Mol Diagn. 2003;5:103–12.PubMedCrossRefGoogle Scholar
  86. 86.
    Jonsson S, Varella-Garcia M, Miller YE, et al. Chromosomal aneusomy in bronchial high-grade lesions is associated with invasive lung cancer. Am J Respir Crit Care Med. 2008;177:342–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Zojer N, Dekan G, Ackermann J, et al. Aneuploidy of chromosome 7 can be detected in invasive lung cancer and associated premalignant lesions of the lung by fluorescence in situ hybridization. Lung Cancer. 2000;28:225–35.PubMedCrossRefGoogle Scholar
  88. 88.
    Pelosi G, Del Curto B, Trubia M, et al. 3q26 Amplification and polysomy of chromosome 3 in squamous cell lesions of the lung: a fluorescence in situ hybridization study. Clin Cancer Res. 2007;13:1995–2004.PubMedCrossRefGoogle Scholar
  89. 89.
    Helfritzsch H, Junker K, Bartel M, et al. Differentiation of positive autofluorescence bronchoscopy findings by comparative genomic hybridisation. Oncol Rep. 2002;9:697–701.PubMedGoogle Scholar
  90. 90.
    Garnis C, MacAuley C, Lam S, et al. Genetic alteration on 8q distinct from MYC in bronchial carcinoma in situ lesions (letter). Lung Cancer. 2004;44:403–4.PubMedCrossRefGoogle Scholar
  91. 91.
    Mao L, Lee JS, Kurie JM, et al. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst. 1997;89:857–62.PubMedCrossRefGoogle Scholar
  92. 92.
    Wistuba II, Lam S, Behrens C, et al. Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst. 1997;89:1366–73.PubMedCrossRefGoogle Scholar
  93. 93.
    Salaün M, Sesboüé R, Moreno-Swirc S, et al. Molecular predictive factors for progression of high-grade preinvasive bronchial lesions. Am J Respir Crit Care Med. 2008;177:880–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Russo AL, Thiagalingam A, Pan H, et al. Differential DNA hypermethylation of critical genes mediates the stage-specific tobacco smoke-induced neoplastic progression of lung cancer. Clin Cancer Res. 2005;11:2466–70.PubMedCrossRefGoogle Scholar
  95. 95.
    Guo M, House MG, Hooker C, et al. Promoter hypermethylation of resected bronchial margins: a field defect of changes? Clin Cancer Res. 2004;10:5131–6.PubMedCrossRefGoogle Scholar
  96. 96.
    Zhang L, Lee JJ, Tang H, et al. Impact of smoking cessation on global gene expression in the bronchial epithelium of chronic smokers. Cancer Prev Res. 2008;1:112–8.CrossRefGoogle Scholar
  97. 97.
    Chari R, Lonergan KM, Ng RT, et al. Effect of active smoking on the human bronchial epithelium transcriptome. BMC Genomics. 2007;8:297.PubMedCrossRefGoogle Scholar
  98. 98.
    Boelens MC, van den Berg A, Fehrmann RS, et al. Current smoking-specific gene expression signature in normal bronchial epithelium is enhanced in squamous cell lung cancer. J Pathol. 2009;218:182–91.PubMedCrossRefGoogle Scholar
  99. 99.
    Wu X, Xiao Z, Chen Z, et al. Differential analysis of two-dimension gel electrophoresis profiles from the normal-metaplasia-dysplasia-carcinoma tissue of human bronchial epithelium. Pathol Int. 2004;54: 765–73.PubMedCrossRefGoogle Scholar
  100. 100.
    Rahman SM, Shyr Y, Yildiz PB, et al. Proteomic patterns of preinvasive bronchial lesions. Am J Respir Crit Care Med. 2005;172:1556–62.PubMedCrossRefGoogle Scholar
  101. 101.
    Mascaux C, Laes JF, Anthoine G, Haller A, et al. Evolution of microRNA expression during human bronchial squamous carcinogenesis. Eur Respir J. 2009;33:352–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Noguchi M. Stepwise progression of pulmonary adenocarcinoma—clinical and molecular implications. Cancer Metastasis Rev. 2010;29:15–21.PubMedCrossRefGoogle Scholar
  103. 103.
    Yatabe Y, Mitsudomi T, Takahashi T. TTF-1 expression in pulmonary adenocarcinomas. Am J Surg Pathol. 2002;26:767–73.PubMedCrossRefGoogle Scholar
  104. 104.
    Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol. 2011;6:244–85.PubMedCrossRefGoogle Scholar
  105. 105.
    Carey FA, Wallace WAH, Fergusson RJ, et al. Alveolar atypical hyperplasia in association with primary pulmonary adenocarcinoma: a clinicopathological study of 10 cases. Thorax. 1992;47:1041–3.PubMedCrossRefGoogle Scholar
  106. 106.
    Kitaguchi S, Takeshima Y, Nishisaka T, et al. Proliferative activity, p53 expression and loss of heterozygosity on 3p, 9p and 17p in atypical adenomatous hyperplasia of the lung. Hiroshima J Med Sci. 1998;47:17–25.PubMedGoogle Scholar
  107. 107.
    Mori M, Kaji M, Tezuka F, et al. Comparative ultrastructural study of atypical adenomatous hyperplasia and adenocarcinoma of the human lung. Ultrastruct Pathol. 1998;22:459–66.PubMedCrossRefGoogle Scholar
  108. 108.
    Kitamura H, Kameda Y, Nakamura N, et al. Proliferative potential and p53 overexpression in precursor and early stage lesions of bronchioloalveolar lung carcinoma. Am J Pathol. 1995;146:876–87.PubMedGoogle Scholar
  109. 109.
    Koga T, Hashimoto S, Sugio K, et al. Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia. Am J Clin Pathol. 2002;117:464–70.PubMedCrossRefGoogle Scholar
  110. 110.
    Yamasaki M, Takeshima Y, Fujii S, et al. Correlation between genetic alterations and histopathological subtypes in bronchiolo-alveolar carcinoma and atypical adenomatous hyperplasia of the lung. Pathol Int. 2000;50:778–85.PubMedCrossRefGoogle Scholar
  111. 111.
    Kerr KM, Fyfe N, Chapman AD, et al. Cell cycle marker MCM2 in peripheral lung adenocarcinoma and its precursors. Lung Cancer. 2003;41:S15.Google Scholar
  112. 112.
    Awaya H, Takeshima Y, Furonaka O, et al. Gene amplification and protein expression of EGFR and HER2 by chromogenic in situ hybridisation and immunohistochemistry in atypical adenomatous hyperplasia and adenocarcinoma of the lung. J Clin Pathol. 2005;58:1076–80.PubMedCrossRefGoogle Scholar
  113. 113.
    Yatabe Y. EGFR mutations and the terminal respiratory unit. Cancer Metastasis Rev. 2010;29:23–36.PubMedCrossRefGoogle Scholar
  114. 114.
    Yoshida Y, Sibata T, Kokubu A, et al. Mutations of the epidermal growth factor receptor gene in atypical adenomatous hyperplasia and bronchioloalveolar carcinoma of the lung. Lung Cancer. 2005;49 Suppl 2:S76.CrossRefGoogle Scholar
  115. 115.
    Kozuki T, Hisamoto A, Tabata M, et al. Mutation of the epidermal growth factor receptor gene in the development of adenocarcinoma of the lung. Lung Cancer. 2007;58:30–5.PubMedCrossRefGoogle Scholar
  116. 116.
    Sakuma Y, Matsukuma S, Yoshihara M, et al. Epidermal growth factor receptor gene mutations in atypical adenomatous hyperplasias of the lung. Mod Pathol. 2007;20:967–73.PubMedCrossRefGoogle Scholar
  117. 117.
    Sakamoto H, Shimizu J, Horio Y, et al. Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas. J Pathol. 2007;212:287–94.PubMedCrossRefGoogle Scholar
  118. 118.
    Ikeda K, Nomori H, Ohba Y, et al. Epidermal growth factor receptor mutations in multicentric lung adenocarcinomas and atypical adenomatous hyperplasias. J Thorac Oncol. 2008;3:467–71.PubMedCrossRefGoogle Scholar
  119. 119.
    Sartori G, Cavazza A, Bertolini F, et al. A subset of lung adenocarcinomas and atypical adenomatous hyperplasia-associated foci are genotypically related: an EGFR, HER2, and K-ras mutational analysis. Am J Clin Pathol. 2008;129:202–10.PubMedCrossRefGoogle Scholar
  120. 120.
    Sagawa M, Saito Y, Fujimura S, et al. K-ras point mutation occurs in the early stage of carcinogenesis in lung cancer. Br J Cancer. 1998;77:720–3.PubMedCrossRefGoogle Scholar
  121. 121.
    Ohshima S, Shimizu Y, Takahama M. Detection of c-Ki-ras gene mutation in paraffin sections of adenocarcinoma and atypical bronchioloalveolar cell hyperplasia of human lung. Virchows Arch. 1994; 424:129–34.PubMedGoogle Scholar
  122. 122.
    Cooper CA, Carey FA, Bubb VJ, et al. The pattern of K-ras mutation in pulmonary adenocarcinoma defines a new pathway of tumour development in the human lung. J Pathol. 1997;181:401–4.PubMedCrossRefGoogle Scholar
  123. 123.
    Westra WH, Baas IO, Hruban RH, et al. K-ras oncogene activation in atypical alveolar hyperplasias of the human lung. Cancer Res. 1996;56:2224–8.PubMedGoogle Scholar
  124. 124.
    Kerr KM, Carey FA, King G, et al. Atypical alveolar hyperplasia: relationship with pulmonary adenocarcinoma, p53 and c-erbB-2 expression. J Pathol. 1994;174:249–56.PubMedCrossRefGoogle Scholar
  125. 125.
    Mori M, Tezuka F, Chiba R, et al. Atypical adenomatous hyperplasia and adenocarcinoma of the human lung. Their heterology in form and analogy in immunohistochemical characteristics. Cancer. 1996;77: 665–74.PubMedCrossRefGoogle Scholar
  126. 126.
    Kurasono Y, Ito T, Kameda Y, et al. Expression of cyclin D1, retinoblastoma gene protein and p16 MTS1 protein in atypical adenomatous hyperplasia and adenocarcinoma of the lung. An immunohistochemical analysis. Virchows Arch. 1998;432:207–15.PubMedCrossRefGoogle Scholar
  127. 127.
    Slebos RJC, Baas IO, Clement MJ, et al. p53 alterations in atypical alveolar hyperplasia of the human lung. Hum Pathol. 1998;29:801–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Nakanishi K, Kawai T, Kumaki F, et al. Survivin expression in atypical adenomatous hyperplasia of the lung. Am J Clin Pathol. 2003;120:712–9.PubMedCrossRefGoogle Scholar
  129. 129.
    Pueblitz S, Hieger LR. Expression of p53 and CEA in atypical adenomatous hyperplasia of the lung (letter). Am J Surg Pathol. 1997;2:867–9.CrossRefGoogle Scholar
  130. 130.
    Kitamura H, Kameda Y, Nakamura N, et al. Atypical adenomatous hyperplasia and bronchoalveolar lung carcinoma. Analysis by morphometry and the expressions of p53 and carcinoembryonic antigen. Am J Surg Pathol. 1996;20:553–62.PubMedCrossRefGoogle Scholar
  131. 131.
    Hayashi H, Miyamoto H, Ito T, et al. Analysis of p21waf1/cip1 expression in normal, premalignant and malignant cells during the development of human lung adenocarcinoma. Am J Pathol. 1997;151: 461–70.PubMedGoogle Scholar
  132. 132.
    Aoyagi Y, Yokose T, Minami Y, et al. Accumulation of losses of heterozygosity and multistep carcinogenesis in pulmonary adenocarcinoma. Cancer Res. 2001;61:7950–4.PubMedGoogle Scholar
  133. 133.
    Sheikh HA, Fuhrer K, Cieply K, et al. p63 expression in assessment of bronchioloalveolar proliferations of the lung. Mod Pathol. 2004;17:1134–40.PubMedCrossRefGoogle Scholar
  134. 134.
    Wu M, Orta L, Gil J, et al. Immunohistochemical detection of XIAP and p63 in adenomatous hyperplasia, atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and well-differentiated adenocarcinoma. Mod Pathol. 2008;21:553–8.PubMedCrossRefGoogle Scholar
  135. 135.
    Au NHC, Gown AM, Cheang M, et al. p63 ­expression in lung carcinoma. A tissue microarray study of 408 cases. Appl Immunohistochem Mol Morphol. 2004;12:240–7.PubMedCrossRefGoogle Scholar
  136. 136.
    Licchesi JD, Westra WH, Hooker CM, et al. Promotor hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung. Clin Cancer Res. 2008;14:2570–8.PubMedCrossRefGoogle Scholar
  137. 137.
    Goto A, Niki T, Moriyama S, et al. Immunohistochemical study of Skp2 and Jab1, two key molecules in the degradation of P27, in lung adenocarcinoma. Pathol Int. 2004;54:675–81.PubMedCrossRefGoogle Scholar
  138. 138.
    Ghaffar H, Sahin F, Sanchez-Cepedes M, et al. LKB1 protein expression in the evolution of glandular ­neoplasia of the lung. Clin Cancer Res. 2003;9: 2998–3003.PubMedGoogle Scholar
  139. 139.
    Kerr KM, MacKenzie SJ, Ramasami S, et al. Expression of Fhit, cell adhesion molecules and matrix metalloproteinases in atypical adenomatous hyperplasia and pulmonary adenocarcinoma. J Pathol. 2004;203:638–44.PubMedCrossRefGoogle Scholar
  140. 140.
    Marchetti A, Pellegrini S, Bertacca G, et al. FHIT and p53 gene abnormalities in bronchioloalveolar carcinomas. Correlations with clinicopathological data and K-ras mutations. J Pathol. 1998;184: 240–6.PubMedCrossRefGoogle Scholar
  141. 141.
    Takamochi K, Ogura T, Yokose T, et al. Molecular analysis of the TSC1 gene in adenocarcinoma of the lung. Lung Cancer. 2004;46:271–81.PubMedCrossRefGoogle Scholar
  142. 142.
    Akyürek N, Memis L, Ekinci O, et al. Survivin expression in pre-invasive lesions and non-small cell lung carcinoma. Virchows Arch. 2006;449:164–70.PubMedCrossRefGoogle Scholar
  143. 143.
    Nakanishi K, Kawai T, Kumaki F, et al. Expression of human telomerase RNA component and telomerase reverse transcriptase mRNA in atypical adenomatous hyperplasia of the lung. Hum Pathol. 2002;33:697–702.PubMedCrossRefGoogle Scholar
  144. 144.
    Nakanishi K, Kawai T, Kumaki F, et al. Expression of mRNAs for telomeric repeat binding factor (TRF)-1 and TRF2 in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Clin Cancer Res. 2003;9:1105–11.PubMedGoogle Scholar
  145. 145.
    Nakanishi K, Kumaki F, Hiroi S, et al. Mre11 expression in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Arch Pathol Lab Med. 2006;130:1330–4.PubMedGoogle Scholar
  146. 146.
    Kayser K, Nwoye JO, Kosjerina Z, et al. Atypical adenomatous hyperplasia of lung: its incidence and analysis of clinical, glycohistochemical and structural features including newly defined growth factor regulators and vascularisation. Lung Cancer. 2003;42:171–82.PubMedCrossRefGoogle Scholar
  147. 147.
    Takigawa N, Ida M, Segawa Y, et al. Expression of cyclooxygenase-2, Fas and Fas ligand in pulmonary adenocarcinoma and atypical adenomatous hyperplasia. Anticancer Res. 2003;23:5069–73.PubMedGoogle Scholar
  148. 148.
    Hosomi Y, Yokose T, Hirose Y, et al. Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precursor lesions of human adenocarcinoma of the lung. Lung Cancer. 2000;30:73–81.PubMedCrossRefGoogle Scholar
  149. 149.
    Saad RS, Liu Y, Han H, et al. Prognostic significance of HER2/neu, p53, and vascular endothelial growth factor expression in early stage conventional adenocarcinoma and bronchioloalveolar carcinoma of the lung. Mod Pathol. 2004;17:1235–42.PubMedCrossRefGoogle Scholar
  150. 150.
    Awaya H, Takeshima Y, Amatya VJ, et al. Loss of expression of E-cadherin and beta-catenin is associated with progression of pulmonary adenocarcinoma. Pathol Int. 2005;55:14–8.PubMedCrossRefGoogle Scholar
  151. 151.
    Kumaki F, Matsui K, Kawai T, et al. Expression of matrix metalloproteinases in invasive pulmonary adenocarcinoma with bronchioloalveolar component and atypical adenomatous hyperplasia. Am J Pathol. 2001;159:2125–35.PubMedCrossRefGoogle Scholar
  152. 152.
    Kitamura H, Oosawa Y, Kawano N, et al. Basement membrane patterns, gelatinase A and tissue inhibitor of metalloproteinase-2 expressions, and stromal fibrosis during the development of peripheral lung adenocarcinoma. Hum Pathol. 1999;30:331–8.PubMedCrossRefGoogle Scholar
  153. 153.
    Iijima T, Minami Y, Nakamura N, et al. MMP-2 activation and stepwise progression of pulmonary adenocarcinoma. Analysis of MMP-2 and MMP-9 with gelatin zymography. Pathol Int. 2004;54:295–301.PubMedCrossRefGoogle Scholar
  154. 154.
    Seki N, Takasu T, Mandai K, et al. Expression of eukaryotic initiation factor 4E in atypical adenomatous hyperplasia and adenocarcinoma of the human peripheral lung. Clin Cancer Res. 2002;8:3046–53.PubMedGoogle Scholar
  155. 155.
    Nakanishi K, Matsuo H, Kanai Y, et al. LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Virchows Arch. 2006;448:142–50.PubMedCrossRefGoogle Scholar
  156. 156.
    Tang X, Shigematsu H, Bekele BN, et al. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer Res. 2005;65:7568–72.PubMedGoogle Scholar
  157. 157.
    Nakayama H, Noguchi M, Tsuchiya R, et al. Clonal growth of atypical adenomatous hyperplasia of the lung: cytofluorometric analysis of nuclear DNA content. Mod Pathol. 1990;3:314–20.PubMedGoogle Scholar
  158. 158.
    Niho S, Yokose T, Suzuki K, et al. Monoclonality of atypical adenomatous hyperplasia of the lung. Am J Pathol. 1999;154:249–54.PubMedCrossRefGoogle Scholar
  159. 159.
    Morandi L, Asioli S, Cavazza A, et al. Genetic relationship among atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and adenocarcinoma of the lung. Lung Cancer. 2007;56:35–42.PubMedCrossRefGoogle Scholar
  160. 160.
    Nakanishi K, Hiroi S, Kawai T, et al. Argyrophilic nucleolar-organiser region counts and DNA status in bronchioloalveolar epithelial hyperplasia and adenocarcinoma of the lung. Hum Pathol. 1998;29: 235–9.PubMedCrossRefGoogle Scholar
  161. 161.
    Yokozaki M, Kodama T, Yokose T, et al. Differentiation of atypical adenomatous hyperplasia and adenocarcinoma of the lung by use of DNA ploidy and morphometric analysis. Mod Pathol. 1996;9:1156–64.PubMedGoogle Scholar
  162. 162.
    Ullmann R, Bongiovanni M, Halbwedl I, et al. Is high-grade adenomatous hyperplasia an early bronchioloalveolar carcinoma? J Pathol. 2003;201: 371–6.PubMedCrossRefGoogle Scholar
  163. 163.
    Suzuki K, Ogura T, Yokose T, et al. Loss of ­heterozygosity in the tuberous sclerosis gene ­associated regions in adenocarcinoma of the lung accompanied by multiple atypical adenomatous hyperplasia. Int J Cancer. 1998;79:384–9.PubMedCrossRefGoogle Scholar
  164. 164.
    Nomori H, Horio H, Naruke T, et al. A case of multiple atypical adenomatous hyperplasia of the lung detected by computed tomography. Jpn J Clin Oncol. 2001;31:514–6.PubMedCrossRefGoogle Scholar
  165. 165.
    Anami Y, Matsuno Y, Yamada T, et al. A case of double primary adenocarcinoma of the lung with multiple atypical adenomatous hyperplasia. Pathol Int. 1998;48:634–40.PubMedCrossRefGoogle Scholar
  166. 166.
    Kerr KM, Galler JS, Hagen JA, et al. The role of DNA methylation in the development and progression of lung adenocarcinoma. Dis Markers. 2007;23:5–30.PubMedGoogle Scholar
  167. 167.
    Du EZ, Goldstraw P, Zacharias J, et al. TTF-1 expression is specific for lung primary in typical and atypical carcinoids: TTF-1-positive carcinoids are predominantly in peripheral location. Hum Pathol. 2004;35:825–31.PubMedCrossRefGoogle Scholar
  168. 168.
    Kerr KM. Pre-existing lung disease and lung cancer. In: Cagle PT, Allen TC, Dacic S, et al., editors. Advances in surgical pathology. Lung cancer, Ch 29. Philadelphia: Lippincott Williams & Wilkins; 2010. p. 275–87.Google Scholar
  169. 169.
    Kawasaki H, Ogura T, Yokose T, et al. p53 gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis. Hum Pathol. 2001;32:1043–9.PubMedCrossRefGoogle Scholar
  170. 170.
    Takahashi T, Munakata M, Ohtsuka Y, et al. Expression and alteration of ras and p53 proteins in patients with lung carcinoma accompanied by idiopathic pulmonary fibrosis. Cancer. 2002;95: 624–33.PubMedCrossRefGoogle Scholar
  171. 171.
    Demopoulos K, Arvanitis DA, Vassilakis DA, et al. MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis. J Cell Mol Med. 2002;6:215–22.PubMedCrossRefGoogle Scholar
  172. 172.
    Murata K, Ota S, Niki T, et al. p63—Key molecule in the early phase of epithelial abnormality in idiopathic pulmonary fibrosis. Exp Mol Pathol. 2007;83:367–76.PubMedCrossRefGoogle Scholar
  173. 173.
    Ruosaari ST, Nymark PE, Aavikko MM, et al. Aberrations of chromosome 19 in asbestos-associated lung cancer and in asbestos-induced micronuclei of bronchial epithelial cells in vitro. Carcinogenesis. 2008;29:913–7.PubMedCrossRefGoogle Scholar
  174. 174.
    Nymark P, Wikman H, Hienonen-Kempas T, et al. Molecular and genetic changes in asbestos-related lung cancer. Cancer Lett. 2008;265:1–15.PubMedCrossRefGoogle Scholar
  175. 175.
    Nymark P, Kettunen E, Aavikko M, et al. Molecular alterations at 9q33.1 and polyploidy in asbestos-related lung cancer. Clin Cancer Res. 2009;15:468–75.PubMedCrossRefGoogle Scholar
  176. 176.
    Kettunen E, Aavikko M, Nymark P, et al. DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure. Br J Cancer. 2009;100:1336–42.PubMedCrossRefGoogle Scholar
  177. 177.
    MacSweeney F, Papagiannopoulos K, Goldstraw P, et al. An assessment of the expanded classification of congenital cystic adenomatoid malformations and their relationship to malignant transformation. Am J Surg Pathol. 2003;27:1139–46.PubMedCrossRefGoogle Scholar
  178. 178.
    Stacher E, Ullmann R, Halbwedl I, et al. Atypical goblet cell hyperplasia in congenital cystic adenomatoid malformation as a possible preneoplasia for pulmonary adenocarcinoma in childhood: a genetic analysis. Hum Pathol. 2004;35:565–70.PubMedCrossRefGoogle Scholar
  179. 179.
    Lantuejoul S, Nicholson AG, Sartori G, et al. Mucinous cells in type 1 pulmonary congenital cystic adenomatoid malformation as mucinous bronchioloalveolar carcinoma precursors. Am J Surg Pathol. 2007;31:961–9.PubMedCrossRefGoogle Scholar
  180. 180.
    Popper HH, el-Shabrawi Y, Wockel W, et al. Prognostic importance of human papilloma virus typing in squamous cell papilloma of the bronchus: comparison of in situ hybridisation and the polymerase chain reaction. Hum Pathol. 1994;25:1191–7.PubMedCrossRefGoogle Scholar
  181. 181.
    Lele SM, Pou AM, Ventura K, et al. Molecular events in the progression of recurrent respiratory papillomatosis to carcinoma. Arch Pathol Lab Med. 2002;126:1184–8.PubMedGoogle Scholar
  182. 182.
    Go C, Schwartz MR, Donovan DT. Molecular transformation of recurrent respiratory papillomatosis: viral typing and p53 overexpression. Ann Otol Rhinol Laryngol. 2003;112:298–302.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Pathology, Aberdeen Royal InfirmaryAberdeen University Medical SchoolAberdeenUK

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