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Abstract

Primary lung cancer is the most frequent cause of death from malignant disease worldwide. In many Western countries the overall incidence of lung cancer shows signs of decreasing, yet the explosion in tobacco consumption in many Asian countries in particular suggests this disease will remain a major worldwide health problem for the foreseeable future. Despite a decline in lung cancer incidence in Western male populations, and, coincident with this, a fall in rates of squamous cell carcinoma, many of these same Western countries are witnessing a continued rise in lung cancer cases in females. At the same time, and probably not entirely unrelated to this change in sex demography, primary adenocarcinoma of the lung is on the increase, although there is evidence of this tumor type also rising in males.

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References

  1. Travis WD, Colby TV, Corrin B, et al., eds. Histological typing of lung and pleural tumours. WHO International histological classification of tumours. 3rd ed. Berlin: Springer, 1999.

    Google Scholar 

  2. Rossle R. Die Narbenkrebse der Lungen. Schweiz Med Wochenschr 1943;73:1200–1203.

    Google Scholar 

  3. Friedrich G. Periphere Lungenkrebse auf dem Boden pleuranaher Narben. Virchows Arch (Pathol Anat) 1939;304:230–247.

    Article  Google Scholar 

  4. Spencer H. Lung scar cancer. In: Shimosato Y, Melamed MD, Nettesheim P, eds. Morphogenesis of lung cancer. Vol 1. Boca Raton, FL: CRC Press, 1982:111–120.

    Google Scholar 

  5. Carroll R. The influence of lung scars on primary lung cancer. J Path Bact 1962;83:293–297.

    Article  CAS  PubMed  Google Scholar 

  6. Raeburn C, Spencer H. A study of the origin and development of lung cancer. Thorax 1953;8:1–10.

    Article  CAS  PubMed  Google Scholar 

  7. Auerbach O, Garfinkel L, Parks VR. Scar cancer of the lung. Increase over a 21 year period. Cancer 1979;43:636–642.

    Article  CAS  PubMed  Google Scholar 

  8. Bakris GL, Mulopulos GP, Korchik R, et al. Pulmonary scar carcinoma. A clinicopathological analysis. Cancer 1983;52:493–497.

    Article  CAS  PubMed  Google Scholar 

  9. Edwards C, Carlile A. Scar adenocarcinoma of the lung: a light and electron microscopic study. J Clin Pathol 1986;39:423–427.

    Article  CAS  PubMed  Google Scholar 

  10. Shimosato Y, Hashimoto T, Kodama T, et al. Prognostic implications of fibrotic focus (scar) in small peripheral lung cancers. Am J Surg Pathol 1980;4:365–373.

    CAS  PubMed  Google Scholar 

  11. Shimosato Y, Kodama T, Kameya T. Morphogenesis of peripheral type adenocarcinoma of the lung. In: Shimosato Y, Melamed MR, Nettesheim P, eds. Morphogenesis of lung cancer. Vol 1. Boca Raton, FL: CRC Press, 1982:65–90.

    Google Scholar 

  12. Suzuki A. Growth characteristics of peripheral type adenocarcinoma in terms of roentgenologic findings. In: Shimosato Y, Melamed MR, Nettesheim P, eds. Morphogenesis of lung cancer. Vol 1. Boca Raton, FL: CRC Press, 1982:91–110.

    Google Scholar 

  13. Cagle PT, Cohle SD, Greenberg SD. Natural history of pulmonary scar cancers. Clinical and pathological implications. Cancer 1985;56:2031–2035.

    Article  CAS  PubMed  Google Scholar 

  14. Madri JA, Carter D. Scar cancers of the lung: origin and significance. Hum Pathol 1984;15:625–631.

    Article  CAS  PubMed  Google Scholar 

  15. Kolin A, Koutoulakis T. Role of arterial occlusion in pulmonary scar cancers. Hum Pathol 1988;19:1161–1167.

    Article  CAS  PubMed  Google Scholar 

  16. Kung ITM, Mok CK, Lui IOL, et al. Pulmonary scar cancer. A pathologic reappraisal. Am J Surg Pathol 1985;9:391–400.

    Article  CAS  PubMed  Google Scholar 

  17. Barsky SH, Huang SJ, Bhuta S. The extracellular matrix of pulmonary scar carcinomas is suggestive of a desmoplastic origin. Am J Pathol 1986;124:412–419.

    CAS  PubMed  Google Scholar 

  18. El-Torkey M, Giltman LI, Dabbous M. Collagens in scar carcinoma of the lung. Am J Pathol 1985;121:322–326.

    CAS  PubMed  Google Scholar 

  19. Yoneda K. Scar carcinomas of the lung in a Histoplasmosis endemic area. Cancer 1990;65:164–168.

    Article  CAS  PubMed  Google Scholar 

  20. Bell ET. Hyperplasia of the pulmonary alveolar epithelium in disease. Am J Pathol 1943;19:901–907.

    PubMed  CAS  Google Scholar 

  21. Geevers EF, Neubuerger KT, Davis CL. The pulmonary alveolar lining under various pathologic conditions in man and animals. Am J Pathol 1943;19:913–937.

    Google Scholar 

  22. Winternitz MC, Wason IM, Mcnamara FP. The pathology of influenza. New Haven: Yale University Press, 1920.

    Google Scholar 

  23. Meyer EC, Liebow AA. Relationship of interstitial pneumonia honeycombing and atypical epithelial proliferation to cancer of the lung. Cancer 1965;18:322–351.

    Article  CAS  PubMed  Google Scholar 

  24. Fraire AE, Greenberg SD. Carcinoma and diffuse interstitial fibrosis of lung. Cancer 1973;31:1078–1086.

    Article  CAS  PubMed  Google Scholar 

  25. Turner-Warwick M, Lebowitz M, Burrows B, et al. Cryptogenic fibrosing alveolitis and lung cancer. Thorax 1980;35:496–499.

    Article  CAS  PubMed  Google Scholar 

  26. Ma Y, Seneviratne CK, Koss M. Idiopathic pulmonary fibrosis and malignancy. Curr Opin Pulm Med 2001;7:278–282.

    Article  CAS  PubMed  Google Scholar 

  27. Stack BH, Choo-Kang YF, Heard BE. The prognosis of cryptogenic fibrosing alveolitis. Thorax 1972;27:535–542.

    Article  CAS  PubMed  Google Scholar 

  28. Matsushita H, Tanaka S, Saiki Y, et al. Lung cancer associated with usual interstitial pneumonia. Pathol Int 1995;45:925–932.

    Article  CAS  PubMed  Google Scholar 

  29. Qunn L, Takemura T, Ikushima S, et al. Hyperplastic epithelial foci in honeycomb lesions in idiopathic pulmonary fibrosis. Virchows Arch 2002;441:271–278.

    Article  PubMed  Google Scholar 

  30. Mizushima Y, Kobayashi M. Clinical characteristics of synchronous multiple lung cancer associated with idiopathic pulmonary fibrosis. A review of Japanese cases. Chest 1995;108:1271–1277.

    Article  Google Scholar 

  31. Samet JM. Does idiopathic pulmonary fibrosis increase lung cancer risk? Am J Respir Crit Care Med 2000;161:1–2.

    CAS  PubMed  Google Scholar 

  32. Hironaka M, Fukayama M. Pulmonary fibrosis and lung carcinoma: a comparative study of metaplastic epithelia in honeycombed areas of usual interstitial pneumonia with or without lung carcinoma. Pathol Int 1999;49:1060–1066.

    Article  CAS  PubMed  Google Scholar 

  33. Sakai S, Ono M, Nishio T, et al. Lung cancer associated with diffuse pulmonary fibrosis: CT-pathologic correlation. J Thorac Imaging 2003;18:67–71.

    Article  PubMed  Google Scholar 

  34. Baumgartner KB, Samet JM, Stidley CA, et al. Cigarette smoking—a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1997;155:242–248.

    CAS  PubMed  Google Scholar 

  35. Hubbard R, Venn A, Lewis S, et al. Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. Am J Respir Crit Care Med 2000;161:5–8.

    CAS  PubMed  Google Scholar 

  36. Aubry MC, Myers JL, Douglas WW, et al. Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis. Mayo Clin Proc 2002;77:763–770.

    Article  PubMed  Google Scholar 

  37. Ardies CM. Inflammation as cause for scar cancers of the lung. Integr Cancer Ther 2003;2:238–246.

    Article  PubMed  Google Scholar 

  38. 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;32:1043–1049.

    Article  CAS  PubMed  Google Scholar 

  39. 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;95:624–633.

    Article  CAS  PubMed  Google Scholar 

  40. 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;6:215–222.

    Article  CAS  PubMed  Google Scholar 

  41. Uematsu K, Yoshimura A, Gemma A, et al. Aberrations in the fragile histidine triad (FHIT) gene in idiopathic pulmonary fibrosis. Cancer Res 2001;61:8527–8533.

    CAS  PubMed  Google Scholar 

  42. Tokarskaya ZB, Okladnikova ND, Belyaeva ZD, et al. The influence of radiation and nonradiation factors on the lung cancer incidence among the workers of the nuclear enterprise. Mayak Health Phys 1995;69:356–366.

    Article  CAS  Google Scholar 

  43. Ohno S, Oshikawa K, Kitamura S, et al. Clinicopathological analysis of interstitial pneumonia associated with collagen vascular disease in patients with lung cancer. (In Japanese. English abstract). Nihon Kyobu Shikkan Gakkai Zasshi 1997;35:1324–1329.

    CAS  PubMed  Google Scholar 

  44. Yang Y, Fujita J, Tokuda M, et al. Lung cancer associated with several connective tissue diseases: with a review of literature. Rheumatol Int 2001;21:106–111.

    Article  CAS  PubMed  Google Scholar 

  45. Peters-Golden M, Wide RA, Hochberg M, et al. Incidence of lung cancer in systemic sclerosis. J Rheumatol 1985;12:1136–1139.

    CAS  PubMed  Google Scholar 

  46. Talbott JH, Barrocas M. Carcinoma of the lung in progressive systemic sclerosis: a tabular review of the literature and a detailed report of the roentgenographic changes in two cases. Semin Arthritis Rheum 1980;9:191–217.

    Article  CAS  PubMed  Google Scholar 

  47. Matteson EL, Hickey AR, Maguire L, et al. Occurrence of neoplasia in patients with rheumatoid arthritis enrolled on DMARD Registry. Rheumatoid Arthritis Azathioprine Registry Steering Committee. J Rheumatol 1991;18:809–814.

    CAS  PubMed  Google Scholar 

  48. Greenberg SD, Roggli VL. Carcinoma of the lung. In: Roggli VL, Greenberg SD, Pratt PC, eds. Pathology of asbestos-associated diseases. Boston: Little, Brown, 1993:189–210.

    Google Scholar 

  49. Mossman BT, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med 1998;157:1666–1680.

    CAS  PubMed  Google Scholar 

  50. Henderson DW, de Klerk NH, Hammar SP, et al. Asbestos and lung cancer: is it attributable to asbestosis or asbestos fibre burden? In: Corrin B, ed. Pathology of lung tumours. Edinburgh: Churchill Livingstone, 1997:83–118.

    Google Scholar 

  51. Jones RN, Hughes JM, Weill H. Asbestos exposure, asbestosis and asbestos-attributable lung cancer. Thorax 1996;51(suppl 2):S9–S15.

    Article  PubMed  Google Scholar 

  52. Churg A. Lung cancer cell type and asbestos exposure. JAMA 1985;253:2984–2985.

    Article  CAS  PubMed  Google Scholar 

  53. Nelson HH, Kelsey KT. The molecular epidemiology of asbestos and tobacco in lung cancer. Oncogene 2002;21:7284–7288.

    Article  CAS  PubMed  Google Scholar 

  54. Katabami M, Dosaka-Akita H, Honma K, et al. Pneumoconiosis-related lung cancers: preferential occurrence from diffuse interstitial fibrosis-type pneumoconiosis. Am J Respir Crit Care Med 2000;162:295–300.

    CAS  PubMed  Google Scholar 

  55. Silicosis and Silicate Disease Committee: Craighead JE (chairman). Diseases associated with exposure to silica and nonfibrous silicate minerals. Arch Pathol Lab Med 1988;112:673–720.

    Google Scholar 

  56. Churg A, Green FHY. Occupational lung disease. In: Thurlbeck WM, Churg AM, eds. Pathology of the lung. 2nd ed. New York: Thieme, 1995:851–929.

    Google Scholar 

  57. Weill H, McDonald JC. Exposure to crystalline silica and risk of lung cancer: the epidemiological evidence. Thorax 1995;51:97–102.

    Article  Google Scholar 

  58. 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;27:1139–1146.

    Article  PubMed  Google Scholar 

  59. Granata C, Gambini C, Balducci T, et al. Bronchioloalveolar carcinoma arising in congenital cystic adenomatoid malformation in a child: a case report and review on malignancies originating in congenital cystic adenomatoid malformation. Pediatr Pulmonol 1998;25:62–66.

    Article  CAS  PubMed  Google Scholar 

  60. Ribet ME, Copin MC, Soots JG, et al. Bronchioloalveolar carcinoma and congenital cystic adenomatoid malformation. Ann Thorac Surg 1995;60:1126–1128.

    Article  CAS  PubMed  Google Scholar 

  61. Kaslovsky RA, Purdy S, Dangman BC, et al. Bronchioloalveolar carcinoma in a child with congenital cystic adenomatoid malformation. Chest 1997;112:548–551.

    Article  CAS  PubMed  Google Scholar 

  62. Benjamin DR, Cahill JL. Bronchioloalveolar carcinoma of the lung and congenital cystic adenomatoid malformation. Am J Clin Pathol 1991;95:889–892.

    CAS  PubMed  Google Scholar 

  63. Sheffield EA, Addis BJ, Corrin B, et al. Epithelial hyperplasia and malignant change in congenital lung cysts. J Clin Pathol 1987;40:612–614.

    Article  CAS  PubMed  Google Scholar 

  64. 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;35:565–570.

    Article  CAS  PubMed  Google Scholar 

  65. Guillou L, Sahli R, Chaubert P, et al. Squamous cell carcinoma of the lung in a non-smoking, nonirradiated patient with juvenile laryngotracheal papillomatosis. Evidence of human papillomavirus-11 DNA in both carcinoma and papillomas. Am J Surg Pathol 1991;15:891–898.

    Article  CAS  PubMed  Google Scholar 

  66. Simma B, Burger R, Uehlinger J, et al. Squamous-cell carcinoma arising in a non-irradiated child with recurrent respiratory papillomatosis. Eur J Pediatr 1993;152:776–778.

    Article  CAS  PubMed  Google Scholar 

  67. DiLorenzo TP, Tamsen A, Abramson AL, et al. Human papillomavirus type 6a DNA in the lung carcinoma of a patient with recurrent laryngeal papillomatosis is characterized by a partial duplication. J Gen Virol 1992;73:423–428.

    Article  CAS  PubMed  Google Scholar 

  68. 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;25:1191–1197.

    Article  CAS  PubMed  Google Scholar 

  69. Prichard MG, Brown PJ, Sterrett GF. Bronchioloalveolar carcinoma arising in longstanding lung cysts. Thorax 1984;39:545–549.

    Article  CAS  PubMed  Google Scholar 

  70. De Perrot M, Pache JC, Spiliopoulos A. Carcinoma arising in congenital lung cysts. J Thorac Cardiovasc Surg 2001;49:184–185.

    Article  Google Scholar 

  71. Bell-Thomson J, Missier P, Sommers SC. Lung carcinoma arising in bronchopulmonary sequestration. Cancer 1979;44:334–339.

    Article  CAS  PubMed  Google Scholar 

  72. Konwaler BE, Reingold IM. Carcinoma arising in bronchiectatic cavities. Cancer 1952;5:525–529.

    Article  CAS  PubMed  Google Scholar 

  73. Tonelli P. A morphological study of nodular lung carcinomas and their possible pathogenesis from a cluster of non-obstructive bronchiectasis. Lung Cancer 1997;17:135–145.

    Article  CAS  PubMed  Google Scholar 

  74. Sawada M, Inase N, Imai M, et al. Chromosome 9p deletion in squamous metaplasia in cystic lesion of the lung. Respirology 2003;8:239–242.

    Article  PubMed  Google Scholar 

  75. Willis RA. The pathology of tumours, fourth edition. London: Butterworths, 1967:1.

    Google Scholar 

  76. Auerbach O, Gere JB, Forman JB, et al. Changes in the bronchial epithelium in relation to smoking and cancer of the lung. N Engl J Med 1957;256:97–104.

    Article  CAS  PubMed  Google Scholar 

  77. Travis WD. Lung. In: Henson DE, Albores-Saavedra J, eds. Pathology of incipient neoplasia. New York: Oxford University Press, 2001:295–316.

    Google Scholar 

  78. Lamb D, Reid L. Goblet cell increases in rat bronchial epithelium after exposure to cigarette and cigar tobacco smoke. Br Med J 1969;1:33–35.

    Article  CAS  PubMed  Google Scholar 

  79. Trump BF, McDowell EM, Glavin F, et al. The respiratory epithelium. III Histogenesis of epidermoid metaplasia and carcinoma in situ in the human. J Natl Cancer Inst 1978;61:563–575.

    CAS  PubMed  Google Scholar 

  80. Auerbach O, Hammond EC, Garfinkel L. Changes in bronchial epithelium in relation to smoking, 1955–1960 vs. 1970–1977. N Engl J Med 1979;300:381–386.

    Article  CAS  PubMed  Google Scholar 

  81. Peters EJ, Morice R, Benner SE, et al. Squamous metaplasia of the bronchial mucosa and its relationship to smoking. Chest 1993;103:1429–1432.

    Article  CAS  PubMed  Google Scholar 

  82. Saccomanno G, Saunders RP, Archer VE, et al. Cancer of the lung—the cytology of sputum prior to the development of carcinoma. Acta Cytol 1965;9:413–423.

    CAS  PubMed  Google Scholar 

  83. Calderon-Garciduenas L, Rodriguez-Alcaraz A, Villarreal-Calderon A, et al. Nasal epithelium as a sentinel for airborne environmental pollution. Toxicol Sci 1998;46:352–364.

    Article  CAS  PubMed  Google Scholar 

  84. Gong H Jr, Fligiel S, Tashkin DP, et al. Tracheobronchial changes in habitual, heavy smokers of marijuana with and without tobacco. Am Rev Respir Dis 1987;136:142–149.

    PubMed  Google Scholar 

  85. Mayne ST Redlich CA, Cullen MR. Dietary vitamin A and prevalence of bronchial metaplasia in asbestosexposed workers. Am J Clin Nutr 1998;68:630–635.

    CAS  PubMed  Google Scholar 

  86. Valentine EH. Squamous metaplasia of the bronchus; a study of metaplastic changes occurring in the epithelium of the major bronchi in cancerous and noncancerous cases. Cancer 1957;10:272–279.

    Article  CAS  PubMed  Google Scholar 

  87. Auerbach O, Stout AP, Hammond EC, et al. Changes in bronchial epithelium in relation to sex, age, residence, smoking and pneumonia. N Engl J Med 1962;267:111–119.

    Article  CAS  PubMed  Google Scholar 

  88. Gazdar AF, Carbone DP. The biology and molecular genetics of lung cancer. Austin, TX: RG Landes; 1994:54.

    Google Scholar 

  89. Melamed MR, Zaman MB. Pathogenesis of epidermoid carcinoma of lung. In: Shimosato Y, Melamed MR, Nettesheim P, eds. Morphogenesis of lung cancer. Volume 1. Boca Raton, FL: CRC Press, 1982:37–64.

    Google Scholar 

  90. Auerbach O, Stout AP, Hammond EC, et al. Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Engl J Med 1961;265:255–267.

    Article  Google Scholar 

  91. Hirsch FR, Prindiville SA, Miller YE, et al. Fluorescence versus white-light bronchoscopy for detection of preneoplastic lesions: a randomised study. J Natl Cancer Inst 2001;93:1385–1391.

    Article  CAS  PubMed  Google Scholar 

  92. Carter D, Marsh BR, Baker RR, et al. Relationship of morphology to clinical presentation in ten cases of early squamous cell carcinoma of the lung. Cancer 1976;37:1389–1396.

    Article  CAS  PubMed  Google Scholar 

  93. Nagamoto N, Saito Y, Sato M, et al. Clinicopathological analysis of 19 cases of isolated carcinoma in situ of the bronchus. Am J Surg Pathol 1993;17:1234–1243.

    Article  CAS  PubMed  Google Scholar 

  94. Woolner LB, Fontana RS, Cortese DA, et al. Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 1984;59:453–466.

    CAS  PubMed  Google Scholar 

  95. Spencer H, Dail DH, Arneaud J. Non-invasive bronchial epithelial papillary tumors. Cancer 1980;45:1486–1497.

    Article  CAS  PubMed  Google Scholar 

  96. Banerjee AK, Rabbitts PH, George J. Lung cancer 3: Fluorescence bronchoscopy: clinical dilemmas and research opportunities. Thorax 2003;58:266–271.

    Article  CAS  PubMed  Google Scholar 

  97. Lam S, Kennedy T, Unger M, et al. Localization of bronchial intraepithelial lesions by fluorescence bronchoscopy. Chest 1998;113:696–702.

    Article  CAS  PubMed  Google Scholar 

  98. Lam S, MacAulay C, LeRiche JC, et al. Detection and localization of early lung cancer by fluorescence bronchoscopy. Cancer 2000;89:2468–2473.

    Article  CAS  PubMed  Google Scholar 

  99. Franklin WA, Wistuba II, Geisinger KR, et al. Squamous dysplasia and carcinoma in situ. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al., eds. World Health Organisation classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004:68–72.

    Google Scholar 

  100. Nuorva K, Soini Y, Kamel D, et al. Concurrent p53 expression in bronchial dysplasias and squamous cell lung carcinomas. Am J Pathol 1993;142:725–732.

    CAS  PubMed  Google Scholar 

  101. Fisseler-Eckhoff A, Prebeg M, Voss B, et al. Extracellular matrix in preneoplastic lesions and early cancer of the lung. Pathol Res Pract 1990;186:95–101.

    CAS  PubMed  Google Scholar 

  102. Keith RL, Miller YE, Gemmill RM, et al. Angiogenic squamous dysplasia in bronchi of individuals at high risk for lung cancer. Clin Cancer Res 2000;6:1616–1625.

    CAS  PubMed  Google Scholar 

  103. Muller KM, Muller G. The ultrastructure of preneoplastic changes in the bronchial mucosa. Curr Top Pathol 1983;73:233–263.

    CAS  PubMed  Google Scholar 

  104. Nasiell M, Auer G, Kato H. Cytological studies in man and animals on development of bronchogenic carcinoma. In: McDowell EM, ed. Lung carcinomas. Edinburgh: Churchill Livingstone, 1987:207–242.

    Google Scholar 

  105. Shibuya K, Hoshino H, Chiyo M, et al. High magnification bronchovideoscopy combined with narrow band imaging could detect capillary loops of angiogenic squamous dysplasia in heavy smokers at high risk for lung cancer. Thorax 2003;58:989–995.

    Article  CAS  PubMed  Google Scholar 

  106. Saccomanno G, Archer VE, Auerbach O, et al. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 1974;33:256–270.

    Article  CAS  PubMed  Google Scholar 

  107. Frost JK, Erozan YS, Gupta PK. Cytopathology. In: National Cancer Institute cooperative early lung cancer group. Atlas of early lung cancer. Tokyo: Igaku-Shoin, 1983.

    Google Scholar 

  108. Tao LC, Chamberlain DW, Delarue NC, et al. Cytologic diagnosis of radiographically occult squamous cell carcinoma of the lung. Cancer 1982;50:1580–1586.

    Article  CAS  PubMed  Google Scholar 

  109. Unattributed. Early lung cancer detection: summary and conclusions. Am Rev Respir Dis 1984;130:565–570.

    Google Scholar 

  110. Woolner LB, David E, Fontana RS, et al. In situ and early invasive bronchogenic carcinoma. Report of 28 cases with postoperative survival data. J Thorac Cardiovasc Surg 1970;60:275–290.

    CAS  PubMed  Google Scholar 

  111. Kennedy TC, Franklin WA, Prindiville SA, et al. High prevalence of occult endobronchial malignancy in high risk patients with moderate sputum atypia. Lung Cancer 2005;49:187–191.

    Article  PubMed  Google Scholar 

  112. Nettesheim P, Klein-Szanto AJP, Yarita T. Experimental models for the study of morphogenesis of lung cancer. In: Shimosato Y, Melamed MR, Nettesheim P, eds. Morphogenesis of lung cancer. Volume 2. Boca Raton, FL: CRC Press, 1982:131–166.

    Google Scholar 

  113. Becci PJ, McDowell EM, Trump BF. The respiratory epithelium. IV. Histogenesis of epidermoid metaplasia and carcinoma in situ in the hamster. J Natl Cancer Inst 1978;61:577–586.

    CAS  PubMed  Google Scholar 

  114. Auer G, Ono J, Nasiell M, et al. Reversibility of bronchial cell atypia. Cancer Res 1982;42:4241–4247.

    CAS  PubMed  Google Scholar 

  115. Hammond EC, Auerbach O, Kirman D, et al. Effects of cigarette smoking in dogs. Arch Environ Health 1970;21:740–753.

    CAS  PubMed  Google Scholar 

  116. Auerbach O. Pathogenesis of lung cancer. Cancer 1961;7:11–21.

    Google Scholar 

  117. Auerbach O, Saccomanno G, Kuschner M, et al. Histologic findings in the tracheobronchial tree of uranium miners and non-miners with lung cancer. Cancer 1978;42:483–489.

    Article  CAS  PubMed  Google Scholar 

  118. Lam S, LeRiche JC, Zheng Y, et al. Sex-related differences in bronchial epithelial changes associated with tobacco smoking. J Natl Cancer Inst 1999;91:691–696.

    Article  CAS  PubMed  Google Scholar 

  119. Frost JK, Ball WC, Levin ML, et al. Sputum cytopathology: use and potential in monitoring the workplace environment by screening for biological effects of exposure. J Occup Med 1986;28:692–703.

    Article  CAS  PubMed  Google Scholar 

  120. Agapitos E, Delsedime L, Kalandidi A, et al. Correlation with early pathological lesions in the bronchial tree with environmental exposures: study objectives and preliminary findings. IARC Sci Publ 1991;112:263–268.

    PubMed  Google Scholar 

  121. Lam S, Hung JY, Kennedy SM, et al. Detection of dysplasia and carcinoma in situ by ratio fluorimetry. Am Rev Respir Dis 1992;146:1458–1461.

    CAS  PubMed  Google Scholar 

  122. Venmans BJ, Van der Linden JC, Elbers JRJ, et al. Observer variability in histopathological reporting of bronchial biopsy specimens: Influence on the results of autofluorescence bronchoscopy in detection of bronchial neoplasia. J Bronchol 2000;7:210–214.

    Article  Google Scholar 

  123. Nicholson AG, Perry LJ, Cury PM, et al. Reproducibility of the WHO/IASLC grading system for pre-invasive squamous lesions of the bronchus: a study of inter-observer and intra-observer variation. Histopathology 2001;38:202–208.

    Article  CAS  PubMed  Google Scholar 

  124. Colby TV, Koss MN, Travis WD. Tumours of the lower respiratory tract. Atlas of tumour pathology. Washington, DC: AFIP, 1995.

    Google Scholar 

  125. Tan KK, Kennedy MM, Kerr KM, et al. Patient survival and bronchial resection line status in primary lung carcinoma. Thorax 1995;50:437P.

    Google Scholar 

  126. Pasic A, Grünberg K, Mooi W, et al. The natural history of carcinoma in situ involving bronchial resection margins. Lung Cancer 2005;49(suppl 2):S57.

    Article  Google Scholar 

  127. Aubert Amoro-Sibilot D, Diab S, et al. Prognostic significance of carcinoma in situ in the vicinity of non small cell resected lung cancer in stage I to IIIA. Lung Cancer 2005;49(suppl 2):S57.

    Article  Google Scholar 

  128. Suprun H, Hjerpe A, Nasiell M, et al. A correlative cytologic study of the incidence of pulmonary cancer and other lung diseases associated with squamous metaplasia of the bronchial epithelium. In: Niebergs HE, ed. Prevention and detection of cancer: Part 2, detection. New York: Marcel Dekker, 1980:1303–1320.

    Google Scholar 

  129. Risse EKJ, Vooijs GP, van’t Hof MA. Diagnostic significance of’ severe dysplasia’ in sputum cytology. Acta Cytol 1988;32:629–634.

    CAS  PubMed  Google Scholar 

  130. Satoh Y, Ishikawa Y, Nakagawa K, et al. A follow-up study of progression from dysplasia to squamous cell carcinoma with immunohistochemical examination of p53 protein overexpression in the bronchi of ex-chromate workers. Br J Cancer 1997;75:678–683.

    CAS  PubMed  Google Scholar 

  131. 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;55:5133–5139.

    CAS  PubMed  Google Scholar 

  132. Venmans BJ, van Boxem TJ, Smit EF, et al. Outcome of bronchial carcinoma in situ. Chest 2000;117:1572–1576.

    Article  CAS  PubMed  Google Scholar 

  133. Sutedja TG, Venmans BJ, Smit EF, et al. Fluorescence bronchoscopy for early detection of lung cancer. A clinical perspective. Lung Cancer 2001;34:157–168.

    Article  CAS  PubMed  Google Scholar 

  134. Sutedja TG, Postmus PE. Personal communication, 2004.

    Google Scholar 

  135. Bota S, Auliac J-B, Paris C, et al. Follow-up of bronchial precancerous lesions and carcinoma in situ using fluorescence endoscopy. Am J Crit Care Med 2001;164:1688–1693.

    CAS  Google Scholar 

  136. 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;15:547–552.

    Article  CAS  PubMed  Google Scholar 

  137. Moro-Sibilot D, Fievet F, Jeanmart M, et al. Clinical prognostic indicators of high-grade pre-invasive bronchial lesions. Eur Respir J 2004;24:24–29.

    Article  CAS  PubMed  Google Scholar 

  138. 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.

    CAS  PubMed  Google Scholar 

  139. Pendelton N, Dixon GR, Burnett HE, et al. Expression of proliferating cell nuclear antigen (PCNA) in dysplasia of the bronchial epithelium. J Pathol 1993;170:169–172.

    Article  Google Scholar 

  140. 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;153:411–416.

    CAS  PubMed  Google Scholar 

  141. Schlake G, Muller KM. Carcinogenesis in bronchial epithelium—an immunohistochemical evaluation of preneoplastic lesions. Virchows Arch 2003;443:291.

    Google Scholar 

  142. Khuri FR, Lee JS, Lippman SM, et al. Modulation of proliferating cell nuclear antigen in the bronchial epithelium of smokers. Cancer Epidemiol Biomark Prev 2001;10:311–318.

    CAS  Google Scholar 

  143. 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;93:1081–1088.

    Article  CAS  PubMed  Google Scholar 

  144. Tormanen U, Nuorva K, Soini Y, et al. Apoptotic activity is increased in parallel with the metaplasia-dysplasiacarcinoma sequence of the bronchial epithelium. Br J Cancer 1999;79:996–1002.

    Article  CAS  PubMed  Google Scholar 

  145. 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.

    Article  CAS  PubMed  Google Scholar 

  146. Fontanini G, Calcinai A, Boldrini L, et al. Modulation of neoangiogenesis in bronchial preneoplastic lesions. Oncol Rep 1999;6:813–817.

    CAS  PubMed  Google Scholar 

  147. 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;200:336–347.

    Article  CAS  PubMed  Google Scholar 

  148. Gazdar AF, Minna JD. Angiogenesis and the multistage development of lung cancers. Clin Cancer Res 2000;6:1611–1612.

    CAS  PubMed  Google Scholar 

  149. Merrick DT, Haney J, Petrunich S, et al. Overexpression of vascular endothelial growth factor and its receptors in bronchial dysplasia demonstrated by quantitative RTPCR analysis. Lung Cancer 2005;48:31–45.

    Article  PubMed  Google Scholar 

  150. Wistuba II, Behrens C, Virmani AK, et al. High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res 2000;60:1949–1960.

    CAS  PubMed  Google Scholar 

  151. Fasano M, Sabatini MT, Wieczorek R, et al. CD44 and its spliced variant in lung tumours. A role in histogenesis? Cancer 1997;80:34–41.

    Article  CAS  PubMed  Google Scholar 

  152. Wimmel A, Kogan E, Ramaswamy A, et al. Variant expression of CD44 in preneoplastic lesions of the lung. Cancer 2001;92:1231–1236.

    Article  CAS  PubMed  Google Scholar 

  153. 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.

    Article  CAS  PubMed  Google Scholar 

  154. Pendleton N, Dixon GR, Green JA, et al. Expression of markers of differentiation in normal bronchial epithelium and bronchial dysplasia. J Pathol 1996;178:146–150.

    Article  CAS  PubMed  Google Scholar 

  155. 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.

    Article  CAS  PubMed  Google Scholar 

  156. 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.

    CAS  PubMed  Google Scholar 

  157. Bejui-Thivolet F, Liagre N, Chignol MC, et al. Detection of human papillomavirus DNA in squamous bronchial metaplasia and squamous cell carcinomas of the lung by in situ hybridization using biotinylated probes in paraffin-embedded specimens. Hum Pathol 1990;21:111–116.

    Article  CAS  PubMed  Google Scholar 

  158. Carey FA, Salter DM, Kerr KM, et al. An investigation into the role of human papillomavirus in endobronchial papillary squamous tumours. Respir Med 1990;84:445–447.

    Article  CAS  PubMed  Google Scholar 

  159. Sekido Y, Fong KM, Minna JD. Molecular genetics of lung cancer. Annu Rev Med 2003;54:73–87.

    Article  CAS  PubMed  Google Scholar 

  160. Hall PA, Lane DP. P53 in tumour pathology: can we trust immunohistochemistry? Revisited. J Pathol 1994;172:1–4.

    Article  CAS  PubMed  Google Scholar 

  161. Vahakangas KH, Samet JM, Metcalf RA, et al. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet 1992;339:576–580.

    Article  CAS  PubMed  Google Scholar 

  162. Sundaresan V, Ganly P, Hasleton PS, et al. P 53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene 1992;7:1989–1997.

    CAS  PubMed  Google Scholar 

  163. Sozzi G, Miozzo M, Donghi R, et al. Deletions of 17p and p53 mutations in preneoplastic lesions of the lung. Cancer Res 1992;52:6079–6082.

    CAS  PubMed  Google Scholar 

  164. Bennett WP, Colby TV, Travis WD, et al. p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res 1993;53:4817–4822.

    CAS  PubMed  Google Scholar 

  165. 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.

    CAS  PubMed  Google Scholar 

  166. 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.

    Article  CAS  PubMed  Google Scholar 

  167. 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;75:504–511.

    Article  CAS  PubMed  Google Scholar 

  168. 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;4:1609–1618.

    CAS  PubMed  Google Scholar 

  169. 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;59:2470–2476.

    CAS  PubMed  Google Scholar 

  170. Martin B, Verdebout J-M, Mascaux C, et al. Expression of p53 in preneoplastic and early neoplastic bronchial lesions. Oncol Rep 2002;9:223–229.

    CAS  PubMed  Google Scholar 

  171. 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;9:2195–2203.

    CAS  PubMed  Google Scholar 

  172. 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;85:341–347.

    Article  CAS  PubMed  Google Scholar 

  173. 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;100:2133–2137.

    Article  CAS  PubMed  Google Scholar 

  174. Chung GT, Sundaresan V, Hasleton P, et al. Clonal evolution of lung tumours. Cancer Res 1996;56:1609–1614.

    CAS  PubMed  Google Scholar 

  175. Sozzi G, Miozzo M, Pastorino U, et al. Genetic evidence for an independent origin for multiple preneoplastic and neoplastic lung lesions. Cancer Res 1995;55:135–140.

    CAS  PubMed  Google Scholar 

  176. 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;91:1863–1868.

    Article  CAS  PubMed  Google Scholar 

  177. Boyle JO, Lonardo F, Chang JH, et al. Multiple highgrade bronchial dysplasia and squamous cell carcinoma: concordant and discordant mutations. Clin Cancer Res 2001;7:259–266.

    CAS  PubMed  Google Scholar 

  178. Sozzi G, Oggionni M, Alasio L, et al. Molecular changes track recurrence and progression of bronchial precancerous lesions. Lung Cancer 2002;37:267–270.

    Article  PubMed  Google Scholar 

  179. Massion PP, Taflan PM, Jamshedur Rahman SM, et al. Significance of p63 amplification and overexpression in lung cancer development and prognosis. Cancer Res 2003;63:7113–7121.

    CAS  PubMed  Google Scholar 

  180. 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;57:5207–5212.

    CAS  PubMed  Google Scholar 

  181. 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.

    CAS  PubMed  Google Scholar 

  182. Geradts J, Fong KM, Zimmerman PV, et al. Loss of Fhit expression in non-small-cell lung cancer: correlation with molecular genetic abnormalities and clinicopathological features. Br J Cancer 2000;82:1191–1197.

    Article  CAS  PubMed  Google Scholar 

  183. Fong KM, Biesterveld EJ, Virmani A, et al. FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res 1997;57:2256–2267.

    CAS  PubMed  Google Scholar 

  184. Wistuba II, Behrens C, Milchgrub S, et al. Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinomas. Oncogene 1999;18:643–650.

    Article  CAS  PubMed  Google Scholar 

  185. Tseng JE, Kemp BL, Khuri FR, et al. Loss of Fhit is frequent in stage I non-small cell lung cancer and in the lungs of chronic smokers. Cancer Res 1999;59:4798–4803.

    CAS  PubMed  Google Scholar 

  186. Zochbauer-Muller S, Wistuba II, Minna JD, et al. Fragile histidine triad (FHIT) gene abnormalities in lung cancer. Clin Lung Cancer 2000;2:141–145.

    Article  CAS  PubMed  Google Scholar 

  187. 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;55:1365–1372.

    CAS  PubMed  Google Scholar 

  188. 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;8:734–744.

    CAS  PubMed  Google Scholar 

  189. Meert A, Martin B, Verdebout J, et al. Is there a role of c-erb-B 2 in the first steps of lung carcinogenesis? Lung Cancer 2005;49(suppl 2):S183.

    Article  Google Scholar 

  190. Franklin WA, Veve R, Hirsch FR, et al. Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol 2002;29:3–14.

    Article  CAS  PubMed  Google Scholar 

  191. West KA, Brognard J, Clark AS, et al. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest 2003;111:81–90.

    CAS  PubMed  Google Scholar 

  192. Tsao AS, McDonnell T, Lam S, et al. Increased phospho-AKT (Ser473) expression in bronchial dysplasia: Implications for lung cancer prevention studies. Cancer Epidemiol Biomark Prev 2003;12:660–664.

    CAS  Google Scholar 

  193. Rodenhuis S, Slebos RJC, Boot AJM, et al. Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 1988;48:5738–5741.

    CAS  PubMed  Google Scholar 

  194. 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;54:5811–5815.

    CAS  PubMed  Google Scholar 

  195. Cooper CA, Carey FA, Bubb VJ, et al. The pattern of Kras mutation in pulmonary adenocarcinoma defines a new pathway of tumour development in the human lung. J Pathol 1997;181:401–404.

    Article  CAS  PubMed  Google Scholar 

  196. Brambilla E, Moro D, Gazzeri S, et al. Alterations of expression of Rb, p16(INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance. J Pathol 1999;188:351–360.

    Article  CAS  PubMed  Google Scholar 

  197. Fong KM, Sekido Y, Gazdar AF, et al. Molecular biology of lung cancer: clinical implications. Thorax 2003;58:892–900.

    Article  CAS  PubMed  Google Scholar 

  198. Brambilla E, Gazzeri S, Moro D, et al. Alterations of Rb pathway (Rb-p16INK4-cyclin D1) in preinvasive bronchial lesions. Clin Cancer Res 1999;5:243–250.

    CAS  PubMed  Google Scholar 

  199. Betticher DC, Heighway J, Thatcher N, et al. Abnormal expression of CCND1 and RB1 in resection margin epithelia of lung cancer patients. Br J Cancer 1997;75:1761–1768.

    CAS  PubMed  Google Scholar 

  200. 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;87:1224–1229.

    Article  CAS  PubMed  Google Scholar 

  201. 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 USA 1998;95:11891–11896.

    Article  CAS  PubMed  Google Scholar 

  202. 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 highrisk patients without invasive cancer. Int J Cancer 2002;100:189–193.

    Article  CAS  PubMed  Google Scholar 

  203. 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;103:153–160.

    Article  CAS  PubMed  Google Scholar 

  204. 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.

    Article  CAS  PubMed  Google Scholar 

  205. Zochenbauer-Muller S, Gazdar AF, Minna JD. Molecular pathogenesis of lung cancer. Annu Rev Physiol 2002;64:681–708.

    Article  Google Scholar 

  206. Sekido Y, Fong KM, Minna JD. Progression in understanding the molecular pathogenesis of human lung cancer. Biochim Biophys Acta 1998;1378:F21–F59.

    CAS  PubMed  Google Scholar 

  207. Walker C, Robertson L, Myskow M, et al. Expression of the bcl-2 protein in normal and dysplastic bronchial epithelium and in lung carcinomas. Br J Cancer 1995;72:164–169.

    CAS  PubMed  Google Scholar 

  208. Martinet N, Alla F, Farre G, et al. Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions. Cancer Res 2000;60:2869–2875.

    CAS  PubMed  Google Scholar 

  209. Snead DR, Perunovic B, Cullen N, et al. hnRNP B1 expression in benign and malignant lung disease. J Pathol 2003;200:88–94.

    Article  CAS  PubMed  Google Scholar 

  210. Wu S, Sato M, Endo C, et al. hnRNP B1 protein may be a possible prognostic factor in squamous cell carcinoma of the lung. Lung Cancer 2003;41:179–186.

    Article  PubMed  Google Scholar 

  211. Yashima K, Litzky LA, Kaiser L, et al. Telomerase expression in respiratory epithelium during the multistage pathogenesis of lung carcinomas. Cancer Res 1997;57:2373–2377.

    CAS  PubMed  Google Scholar 

  212. 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;92:849–855.

    Article  CAS  PubMed  Google Scholar 

  213. 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;109:412–417.

    Article  CAS  PubMed  Google Scholar 

  214. Lantuejoul S, Soria JC, Morat L, et al. Telomere shortening and telomerase reverse transcriptase expression in preinvasive bronchial lesions. Clin Cancer Res 2005;11:2074–2082.

    Article  CAS  PubMed  Google Scholar 

  215. 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;73:203–209.

    CAS  PubMed  Google Scholar 

  216. 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;28:225–235.

    Article  CAS  PubMed  Google Scholar 

  217. Helfritzsch H, Junker K, Bartel M, et al. Differentiation of positive autofluorescence bronchoscopy findings by comparative genomic hybridisation. Oncol Rep 2002;9:697–701.

    CAS  PubMed  Google Scholar 

  218. 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;44:403–404.

    Article  PubMed  Google Scholar 

  219. Mao L, Lee JS, Kurie JM, et al. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst 1997;89:857–862.

    Article  CAS  PubMed  Google Scholar 

  220. Wistuba II, Lam S, Behrens C, et al. Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst 1997;89:1366–1373.

    Article  CAS  PubMed  Google Scholar 

  221. Chung GT, Sundaresan V, Hasleton P, et al. Sequential molecular genetic changes in lung cancer development. Oncogene 1995;11:2591–2598.

    CAS  PubMed  Google Scholar 

  222. Hung J, Kishimoto Y, Sugio K, et al. Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. JAMA 1995;273:558–563.

    Article  CAS  PubMed  Google Scholar 

  223. 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;59:1973–1979.

    CAS  PubMed  Google Scholar 

  224. Wistuba II, Mao L, Gazdar AF. Smoking molecular damage in bronchial epithelium. Oncogene 2002;21:7298–7306.

    Article  CAS  PubMed  Google Scholar 

  225. 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;22:8677–8687.

    Article  CAS  PubMed  Google Scholar 

  226. Smith SL, Gugger M, Hoban P, et al. S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell carcinomas. Br J Cancer 2004;91:1515–1524.

    CAS  PubMed  Google Scholar 

  227. Minna JD, Fong K, Zochbauer-Muller S, et al. Molecular pathogenesis of lung cancer and potential translational applications. Cancer J 2002;8(suppl 1):S41–S46.

    PubMed  Google Scholar 

  228. Brambilla E, Moro D, Veale D, et al. Basal cell (basaloid) carcinoma of the lung. A new morphologic and phenotypic entity with separate prognostic significance. Hum Pathol 1992;23:993–1003.

    Article  CAS  PubMed  Google Scholar 

  229. Sturm N, Lantuejoul S, Laverriere M-H, et al. Thyroid transcription factor 1 and cytokeratins 1,5,10,14 (34βE12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung. Hum Pathol 2001;32:918–925.

    Article  CAS  PubMed  Google Scholar 

  230. Travis WD, Travis LB, Devesa SS. Lung cancer. Cancer 1995;75(suppl):191–202.

    Article  CAS  PubMed  Google Scholar 

  231. Harkness EF, Brewster DH, Kerr KM, et al. Changing trends in incidence of lung cancer by histological type in Scotland. Int J Cancer 2002;102:179–183.

    Article  CAS  PubMed  Google Scholar 

  232. Miller RR, Nelems B, Evans KG, et al. Glandular neoplasia of the lung. A proposed analogy to colonic tumours. Cancer 1988;61:1009–1014.

    Article  CAS  PubMed  Google Scholar 

  233. Nakanishi K. Alveolar epithelial hyperplasia and adenocarcinoma of the lung. Arch Pathol Lab Med 1990;114:363–368.

    CAS  PubMed  Google Scholar 

  234. 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;47:1041–1043.

    Article  CAS  PubMed  Google Scholar 

  235. Weng S-Y, Tsuchiya E, Kasuga T, et al. Incidence of atypical bronchioloalveolar cell hyperplasia of the lung: relation to histological subtypes of lung cancer. Virchows Arch A Pathol Anat 1992;420:463–471.

    Article  CAS  Google Scholar 

  236. Weng S, Tsuchiya E, Satoh Y, et al. Multiple atypical adenomatous hyperplasia of type II pneumocytes and bronchioloalveolar carcinoma. Histopathology 1990;16:101–103.

    Article  CAS  PubMed  Google Scholar 

  237. 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;3:314–320.

    CAS  PubMed  Google Scholar 

  238. Miller RR. Bronchioloalveolar cell adenomas. Am J Surg Pathol 1990;14:904–912.

    Article  CAS  PubMed  Google Scholar 

  239. Nakahara R, Yokose T, Nagai K, et al. Atypical adenomatous hyperplasia of the lung: a clinicopathological study of 118 cases including cases with multiple atypical adenomatous hyperplasia. Thorax 2001;56:302–305.

    Article  CAS  PubMed  Google Scholar 

  240. Chapman AD, Kerr KM. The association between atypical adenomatous hyperplasia and primary lung cancer. Br J Cancer 2000;83:632–636.

    Article  CAS  PubMed  Google Scholar 

  241. Kerr KM, Fraire AE, Pugatch B, et al. Atypical adenomatous hyperplasia. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al, eds. World Health Organisation classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004:73–75.

    Google Scholar 

  242. Kitamura H, Kameda Y, Ito T, et al. Cytodifferentiation of atypical adenomatous hyperplasia and bronchioloalveolar lung carcinoma: immunohistochemical and ultrastructural studies. Virchows Arch 1997;431:415–424.

    Article  CAS  PubMed  Google Scholar 

  243. Kitamura H, Kameda Y, Ito T, et al. Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma. Am J Clin Pathol 1999;111:610–622.

    CAS  PubMed  Google Scholar 

  244. Mori M, Kaji M, Tezuka F, et al. Comparative ultrastructural study of atypical adenomatous hyperplasia and adenocarcinoma of the human lung. Ultrastruct Pathol 1998;22:459–466.

    Article  CAS  PubMed  Google Scholar 

  245. Osanai M, Igarashi T, Yoshida Y. Unique cellular features in atypical adenomatous hyperplasia of the lung: ultrastructural evidence of its cytodifferentiation. Ultrastruct Pathol 2001;25:367–373.

    Article  CAS  PubMed  Google Scholar 

  246. Kodama T, Biyajima S, Watanabe S, et al. Morphometric study of adenocarcinomas and hyperplastic epithelial lesions in the peripheral lung. Am J Clin Pathol 1986;85:146–151.

    CAS  PubMed  Google Scholar 

  247. 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;146:876–887.

    CAS  PubMed  Google Scholar 

  248. Kerr KM. Atypical adenomatous hyperplasia versus nonmucinous bronchioloalveolar carcinoma. A spectrum of neoplasia in the lung periphery. Lung Cancer 2000;29(S2):94–95.

    Google Scholar 

  249. 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;20:553–562.

    Article  CAS  PubMed  Google Scholar 

  250. 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.

    Article  PubMed  Google Scholar 

  251. Kerr KM. Morphology and genetics of preinvasive pulmonary disease. Curr Diag Pathol 2004;10:259–268.

    Article  Google Scholar 

  252. Kerr KM. Adenomatous hyperplasia and the origin of peripheral adenocarcinoma of the lung. In: Corrin B, ed. Pathology of lung tumours. Edinburgh: Churchill Livingstone, 1997:119–134.

    Google Scholar 

  253. Noguchi M, Morokawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 1995;75:2844–2852.

    Article  CAS  PubMed  Google Scholar 

  254. Kurokawa T, Matsuno Y, Noguchi M, et al. Surgically curable “early” adenocarcinoma in the periphery of the lung. Am J Surg Pathol 1994;18:431–438.

    Article  CAS  PubMed  Google Scholar 

  255. Noguchi M. Personal communication, 2003.

    Google Scholar 

  256. Colby TV, Noguchi M, Henschke C, et al. Adenocarcinoma. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al., eds. World Health Organisation classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004:35–44.

    Google Scholar 

  257. Nomori H, Ohtsuka T, Naruke T, et al. Differentiating between atypical adenomatous hyperplasia and bronchioloalveolar carcinoma using the computed tomography number histogram. Ann Thorac Surg 2003;76:867–871.

    Article  PubMed  Google Scholar 

  258. Noguchi M, Kodama T, Shimosato Y, et al. Papillary adenoma of type 2 pneumocytes. Am J Surg Pathol 1986;10:134–139.

    Article  CAS  PubMed  Google Scholar 

  259. Yousem SA, Hochholzer L. Alveolar adenoma. Hum Pathol 1986;17:1066–1071.

    Article  CAS  PubMed  Google Scholar 

  260. Lantuejoul S, Ferretti G, Negoescu A, et al. Multifocal alveolar hyperplasia associated with lymphangioleiomyomatosis in tuberous sclerosis. Histopathology 1997;30:570–575.

    Article  CAS  PubMed  Google Scholar 

  261. Muir TE, Leslie KO, Popper H, et al. Micronodular pneumocyte hyperplasia. Am J Surg Pathol 1998;22:465–472.

    Article  CAS  PubMed  Google Scholar 

  262. Travis WD, Linnoila RI, Horowitz M, et al. Pulmonary nodules resembling bronchioloalveolar carcinoma in adolescent cancer patients. Mod Pathol 1998;1:372–377.

    Google Scholar 

  263. Yanagisawa M. A histopathological study of proliferative changes of the epithelial components of the lung. A contribution to the histogenesis of pulmonary carcinoma (in Japanese). Jpn J Cancer Clin 1959;5:667–680.

    Google Scholar 

  264. Sterner DJ, Masuko M, Roggli VL, et al. Prevalence of pulmonary atypical alveolar cell hyperplasia in an autopsy population: a study of 100 cases. Mod Pathol 1997;10:469–473.

    CAS  PubMed  Google Scholar 

  265. Yokose T, Ito Y, Ochiai A. High prevalence of atypical adenomatous hyperplasia of the lung in autopsy specimens from elderly patients with malignant neoplasms. Lung Cancer 2000;29:125–130.

    Article  CAS  PubMed  Google Scholar 

  266. Yokose T, Doi M, Tanno K, Yamazaki K, Ochiai A. Atypical adenomatous hyperplasia of the lung in autopsy cases. Lung Cancer 2001;33:155–161.

    Article  CAS  PubMed  Google Scholar 

  267. Morinaga S, Shimosato Y. Microcancer of the bronchus and lung: pathology of the microadenocarcinoma in the periphery of the lung (in Japanese). Pathol Clin Med 1987;5(suppl):74–80.

    Google Scholar 

  268. Kodama T, Nishiyama H, Nishiwaki Y, et al. Histopathological study of adenocarcinoma and hyperplastic epithelial lesion of the lung (in Japanese, abstract in English). Haigan (Lung Cancer) 1988;28:325–333.

    Google Scholar 

  269. Noguchi M, Shimosato Y. The development and progression of adenocarcinoma of the lung. In: Hansen HH, ed. Lung cancer. Boston: Kluwer Academic, 1994:131–142.

    Google Scholar 

  270. 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;48:634–640.

    Article  CAS  PubMed  Google Scholar 

  271. Suzuki K, Takahashi K, Yoshida J, et al. Synchronous double primary lung carcinomas associated with multiple atypical adenomatous hyperplasia. Lung Cancer 1998;19:131–139.

    Article  CAS  PubMed  Google Scholar 

  272. Dohmoto K, Fujita J, Ohtsuki Y, et al. Synchronous four primary lung adenocarcinoma associated with multiple atypical adenomatous hyperplasia. Lung Cancer 2000;27:125–130.

    Article  CAS  PubMed  Google Scholar 

  273. Takamochi K, Ogura T, Suzuki K. Loss of heterozygosity on chromosomes 9q and 16p in atypical adenomatous hyperplasia concomitant with adenocarcinoma of the lung. Am J Pathol 2001;159:1941–1948.

    CAS  PubMed  Google Scholar 

  274. Takigawa N, Segawa Y, Nakata M, et al. Clinical investigation of atypical adenomatous hyperplasia of the lung. Lung Cancer 1999;25:115–121.

    Article  CAS  PubMed  Google Scholar 

  275. Kitagawa H, Goto A, Niki T, et al. Lung adenocarcinoma associated with atypical adenomatous hyperplasia. A clinicopathological study with special reference to smoking and cancer multiplicity. Pathol Int 2003;53:823–827.

    Article  PubMed  Google Scholar 

  276. Chapman AD, Thetford D, Kerr KM. Pathological and clinical investigation of pulmonary atypical adenomatous hyperplasia and its association with primary lung adenocarcinoma Lung Cancer 2000;29(S1):215–216.

    Article  Google Scholar 

  277. 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;9:1156–1164.

    CAS  PubMed  Google Scholar 

  278. Mori M, Chiba R, Takahashi T. Atypical adenomatous hyperplasia of the lung and its differentiation from adenocarcinoma. Characterisation of atypical cells by morphometry and multivariate cluster analysis. Cancer 1993;72:2331–2340.

    Article  CAS  PubMed  Google Scholar 

  279. 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;29:235–239.

    Article  CAS  PubMed  Google Scholar 

  280. 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.

    CAS  PubMed  Google Scholar 

  281. 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;432:207–215.

    Article  CAS  PubMed  Google Scholar 

  282. 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;50:778–785.

    Article  CAS  PubMed  Google Scholar 

  283. 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 

  284. Rao SK, Fraire AE. Alveolar cell hyperplasia in association with adenocarcinoma of lung. Mod Pathol 1995;9:99–108.

    Google Scholar 

  285. 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;77:665–674.

    Article  CAS  PubMed  Google Scholar 

  286. Stenhouse G, Fyfe N, King G, et al. Thyroid transcription factor 1 in pulmonary adenocarcinoma. J Clin Pathol 2004;57:383–387.

    Article  CAS  PubMed  Google Scholar 

  287. 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;159:2125–2135.

    CAS  PubMed  Google Scholar 

  288. 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;203:638–644.

    Article  CAS  PubMed  Google Scholar 

  289. 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;30:331–338.

    Article  CAS  PubMed  Google Scholar 

  290. 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.

    Article  CAS  PubMed  Google Scholar 

  291. 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;42:171–182.

    Article  PubMed  Google Scholar 

  292. 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;55:14–18.

    Article  CAS  PubMed  Google Scholar 

  293. Awaya H, Takeshima Y, Yamasaki M, et al. Expression of MUC1, MUC2, MUC5AC, and MUC6 in atypical adenomatous hyperplasia, bronchioloalveolar carcinoma, adenocarcinoma with mixed subtypes, and mucinous bronchioloalveolar carcinoma of the lung. Am J Clin Pathol 2004;121:644–653.

    Article  CAS  PubMed  Google Scholar 

  294. Kerr KM, Carey FA, King G, et al. Atypical alveolar hyperplasia: relationship with pulmonary adenocarcinoma, p53 and c-erbB-2 expression. J Pathol 1994;174:249–256.

    Article  CAS  PubMed  Google Scholar 

  295. Yatabe Y, Kosaka T, Takahashi T, et al. EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol 2005;29:633–639.

    Article  PubMed  Google Scholar 

  296. 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.

    Article  Google Scholar 

  297. Hida T, Yatabe Y, Achiwa H, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998;58:3761–3764.

    CAS  PubMed  Google Scholar 

  298. 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;23:5069–5073.

    CAS  PubMed  Google Scholar 

  299. 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.

    Article  CAS  PubMed  Google Scholar 

  300. Schreinemachers DM, Everson RB. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 1994;5:138–146.

    Article  CAS  PubMed  Google Scholar 

  301. 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;8:3046–3053.

    CAS  PubMed  Google Scholar 

  302. 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.

    Article  CAS  PubMed  Google Scholar 

  303. Nakanishi K, Kawai T, Kumaki F, et al. Survivin expression in atypical adenomatous hyperplasia of the lung. Am J Clin Pathol 2003;120:712–719.

    Article  PubMed  Google Scholar 

  304. Barrios R, Khoor A, Ostrowski B, et al. Analysis of p27 expression in lung adenocarcinoma vs. adenomatous hyperplasia of the lung. Mod Pathol 2000;13:206A.

    Google Scholar 

  305. 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;54:675–681.

    Article  CAS  PubMed  Google Scholar 

  306. Slebos RJC, Baas IO, Clement MJ, et al. p53 alterations in atypical alveolar hyperplasia of the human lung. Hum Pathol 1998;29:801–808.

    Article  CAS  PubMed  Google Scholar 

  307. Pueblitz S, Hieger LR. Expression of p53 and CEA in atypical adenomatous hyperplasia of the lung (letter). Am J Surg Pathol 1997;2:867–869.

    Article  Google Scholar 

  308. 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;151:461–470.

    CAS  PubMed  Google Scholar 

  309. Aoyagi Y, Yokose T, Minami Y, et al. Accumulation of losses of heterozygosity and multistep carcinogenesis in pulmonary adenocarcinoma. Cancer Res 2001;61:7950–7954.

    CAS  PubMed  Google Scholar 

  310. Sheikh HA, Fuhrer K, Cieply K, et al. p63 expression in assessment of bronchioloalveolar proliferations of the lung. Mod Pathol 2004;17:1134–1140.

    Article  CAS  PubMed  Google Scholar 

  311. Johnson L, Mercer K, Greenbaum D, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 2001;410:1111–1116.

    Article  CAS  PubMed  Google Scholar 

  312. Meuwissen R, Linn SC, van der Valk M, et al. Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene. Oncogene 2001;20:6551–6558.

    Article  CAS  PubMed  Google Scholar 

  313. Ohshima S, Shimizu Y, Takahama M. Detection of c-Kiras gene mutation in paraffin sections of adenocarcinoma and atypical bronchioloalveolar cell hyperplasia of human lung. Virchows Arch 1994;424:129–134.

    CAS  PubMed  Google Scholar 

  314. 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;77:720–723.

    CAS  PubMed  Google Scholar 

  315. Westra WH, Baas IO, Hruban RH, et al. K-ras oncogene activation in atypical alveolar hyperplasias of the human lung. Cancer Res 1996;56:2224–2228.

    CAS  PubMed  Google Scholar 

  316. Niho S, Yokose T, Suzuki K, et al. Monoclonality of atypical adenomatous hyperplasia of the lung. Am J Pathol 1999;154:249–254.

    CAS  PubMed  Google Scholar 

  317. Ullmann R, Bongiovanni M, Halbwedl I, et al. Is high-grade adenomatous hyperplasia an early bronchioloalveolar carcinoma? J Pathol 2003;201:371–376.

    Article  CAS  PubMed  Google Scholar 

  318. 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;184:240–246.

    Article  CAS  PubMed  Google Scholar 

  319. Sasatomi E, Johnson LR, Aldeeb DN et al. Genetic profile of cumulative mutational damage associated with early pulmonary adenocarcinoma: bronchioloalveolar carcinoma vs. stage I invasive adenocarcinoma. Am J Surg Pathol 2004;28:1280–1288.

    Article  PubMed  Google Scholar 

  320. 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;79:384–389.

    Article  CAS  PubMed  Google Scholar 

  321. Takamochi K, Ogura T, Yokose T, et al. Molecular analysis of the TSC1 gene in adenocarcinoma of the lung. Lung Cancer 2004;46:271–281.

    Article  PubMed  Google Scholar 

  322. 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;31:514–516.

    Article  CAS  PubMed  Google Scholar 

  323. Frasca JM, Auerbach O, Parks VR, et al. Alveolar cell hyperplasia in the lungs of smoking dogs. Exp Mol Pathol 1974;21:300–312.

    Article  CAS  PubMed  Google Scholar 

  324. Foster C, Kerr KM. Unpublished observations.

    Google Scholar 

  325. Attenoos R. Personal communication.

    Google Scholar 

  326. Yousem SA, Finkelstein SD, Swalsky PA, et al. Absence of jaagsiekte sheep retrovirus DNA and RNA in bronchioloalveolar and conventional human pulmonary adenocarcinoma by PCR and RT-PCR analysis. Hum Pathol 2001;32:1039–1042.

    Article  CAS  PubMed  Google Scholar 

  327. Meuwissen R, Lin SC, Linnoila RI, et al. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 2003;4:181–189.

    Article  CAS  PubMed  Google Scholar 

  328. Nadav Y, Pastorino U, Nicholson AG. Multiple synchronous lung cancers and atypical adenomatous hyperplasia in Li-Fraumeni syndrome. Histopathology 1998;33:52–54.

    Article  CAS  PubMed  Google Scholar 

  329. Gazdar AF, Minna JD. Cigarettes, sex and lung adenocarcinoma. J Natl Cancer Inst 1997;89:1563–1565.

    Article  CAS  PubMed  Google Scholar 

  330. Thun MJ, Lally CA, Flannery JT, et al. Cigarette smoking and changes in the histopathology of lung cancer. J Natl Cancer Inst 1997;89:1580–1586.

    Article  CAS  PubMed  Google Scholar 

  331. Aoki T, Nakata H, Watanabe H, et al. Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumour doubling time. Am J Roengenol 2000;174:763–768.

    CAS  Google Scholar 

  332. Asamura H, Suzuki K, Watanabe S, et al. A clinicopathological study of resected subcentimeter lung cancers: a favourable prognosis for ground glass opacity lesions. Ann Thorac Surg 2003;76:1016–1022.

    Article  PubMed  Google Scholar 

  333. Logan PM, Miller RR, Evans K, et al. Bronchogenic carcinoma and coexistent bronchioloalveolar cell adenomas. Assessment of radiologic detection and follow-up in 28 patients. Chest 1996;109:713–717.

    Article  CAS  PubMed  Google Scholar 

  334. Suzuki K, Nagai K, Yoshida J, et al. The prognosis of resected lung carcinoma associated with atypical adenomatous hyperplasia: a comparison of the prognosis of well-differentiated adenocarcinoma associated with atypical adenomatous hyperplasia and intrapulmonary metastasis. Cancer 1997;79:1521–1526.

    Article  CAS  PubMed  Google Scholar 

  335. Kerr KM. Pulmonary preinvasive neoplasia. J Clin Pathol 2001;54:257–271.

    Article  CAS  PubMed  Google Scholar 

  336. Mori M, Rao SK, Popper HH, et al. Atypical adenomatous hyperplasia of the lung: A probable forerunner in the development of adenocarcinoma of the lung. Mod Pathol 2001;14:72–84.

    Article  CAS  PubMed  Google Scholar 

  337. Nakano K, Iyama K, Mori T, et al. Loss of alveolar basement membrane type IV collagen α3, α4, α5 chains in bronchioloalveolar carcinoma of the lung. J Pathol 200 2001;194:420–427.

    Article  CAS  Google Scholar 

  338. Suzuki K, Yokose T, Yoshida J, et al. Prognostic significance of the size of central fibrosis in peripheral adenocarcinoma of the lung. Ann Thorac Surg 2000;69:893–897.

    Article  CAS  PubMed  Google Scholar 

  339. Ritter JH. Pulmonary atypical adenomatous hyperplasia. A histological lesion in search of usable criteria and clinical significance. Am J Clin Pathol 1999;111:587–589.

    CAS  PubMed  Google Scholar 

  340. Ullman R, Bongiovanni M, Halbwedl I, et al. Bronchiolar columnar cell dysplasia—genetic analysis of a novel preneoplastic lesion of peripheral lung. Virchows Arch 2003;442:429–436.

    Google Scholar 

  341. Aguayo SM, Miller YE, Waldron JA, et al. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airway disease. N Engl J Med 1992;327:1285–1288.

    Article  CAS  PubMed  Google Scholar 

  342. Sheerin N, Harrison NK, Sheppard, et al. Obliterative bronchiolitis caused by multiple tumourlets and microcarcinoids successfully treated by single lung transplantation. Thorax 1995;50:207–209.

    Article  CAS  PubMed  Google Scholar 

  343. Jessurun J, Manivel JC, Simpson R. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells (IDHPNC): a consequence of diffuse bronchiolitis. Lab Invest 1994;70:151A.

    Google Scholar 

  344. Armas OA, White DA, Erlandson RA. Diffuse idiopathic pulmonary neuroendocrine cell proliferation presenting as interstitial lung disease. Am J Surg Pathol 1995;19:963–970.

    Article  CAS  PubMed  Google Scholar 

  345. Brown MJ, English J, Muller NL. Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT-pathologic correlation. Am J Roentgenol 1997;168:1561–1562.

    CAS  Google Scholar 

  346. Lee JS, Brown KK, Cool C, et al. Diffuse pulmonary neuroendocrine cell hyperplasia: Radiologic and clinical features. J Comput Assist Tomogr 2002;26:180–184.

    Article  PubMed  Google Scholar 

  347. Felton WL, Liebow AA, Lindskog GF. Peripheral and multiple bronchial adenomas. Cancer 1953;6:555–567.

    Article  PubMed  Google Scholar 

  348. Gmelich JT, Bensch KG, Liebow AA. Cells of Kulchitsky type in bronchioles and their relation to the origin of peripheral carcinoid tumours. Lab Invest 1967;17:88–98.

    CAS  PubMed  Google Scholar 

  349. Miller MA, Mark GJ, Kanarek D. Multiple peripheral pulmonary carcinoids and tumourlets of carcinoid type, with restrictive and obstructive lung disease. Am J Med 1978;65:373–378.

    Article  CAS  PubMed  Google Scholar 

  350. Cohen AJ, King TE, Gilman LB, et al. High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells. Am J Respir Crit Care Med 1998;158:1593–1599.

    CAS  PubMed  Google Scholar 

  351. Miller RR, Muller NL. Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumours. Am J Surg Pathol 1995;19:653–658.

    Article  CAS  PubMed  Google Scholar 

  352. Whitwell F. Tumourlets of the lung. J Path Bact 1955;70:529–541.

    Article  CAS  PubMed  Google Scholar 

  353. Churg A, Warnock ML. Pulmonary tumourlet. A form of peripheral carcinoid. Cancer 1976;37:1469–1477.

    Article  CAS  PubMed  Google Scholar 

  354. Kay S. Histologic and histogenetic observations on the peripheral adenoma of the lung. Arch Pathol 1958;65:395–402.

    CAS  Google Scholar 

  355. Hausman DH, Weimann RB. Pulmonary tumourlet with hilar lymph node metastases. Cancer 1967;20:1515–1519.

    Article  CAS  PubMed  Google Scholar 

  356. D’Agati VD, Perzin KH. Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node. Report of a case and review of the literature. Cancer 1985;55:2472–2476.

    Article  PubMed  Google Scholar 

  357. Bonikos DS, Bensch KG, Jamplis RW. Peripheral pulmonary carcinoid tumours. Cancer 1976;37:1977–1998.

    Article  CAS  PubMed  Google Scholar 

  358. Johnson DE, Lock JE, Elde RP, et al. Pulmonary neuroendocrine cells in hyaline membrane disease and bronchopulmonary dysplasia. Pediatr Res 1982;16:446–454.

    CAS  PubMed  Google Scholar 

  359. Johnson DE, Wobken JD, Landrum BG. Changes in bombesin, calcitonin, and serotonin immunoreactive pulmonary neuroendocrine cells in cystic fibrosis and after prolonged mechanical ventilation. Am Rev Respir Dis 1988;137:123–131.

    CAS  PubMed  Google Scholar 

  360. Watanabe H, Kobayashi H, Honma K, et al. Diffuse panbronchiolitis with multiple tumourlets. A quantitative study of the Kultschitzky cells and the clusters. Acta Pathol Jpn 1985;35:1221–1231.

    CAS  PubMed  Google Scholar 

  361. Gosney JR, Sissons MC, Allibone RO, et al. Pulmonary endocrine cells in chronic bronchitis and emphysema. J Pathol 1989;157:127–133.

    Article  CAS  PubMed  Google Scholar 

  362. Aguayo SM, King TE Jr, Waldron JA, Jr, et al. Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. J Clin Invest 1990;86:838–844.

    Article  CAS  PubMed  Google Scholar 

  363. Pelosi G, Zancanaro C, Sbabo L, et al. Development of innumerable neuroendocrine tumourlets in pulmonary lobe scarred by intralobar sequestration. Immunohistochemical and ultrastructural study of an unusual case. Arch Pathol Lab Med 1992;116:1167–1174.

    CAS  PubMed  Google Scholar 

  364. Ranchod M. The histogenesis and development of pulmonary tumourlets. Cancer 1977;39:1135–1145.

    Article  CAS  PubMed  Google Scholar 

  365. Sturm N, Rossi G, Lantuejoul S, et al. Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids. Hum Pathol 2002;33:175–182.

    Article  PubMed  Google Scholar 

  366. 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;35:825–831.

    Article  CAS  PubMed  Google Scholar 

  367. Salyer DC, Salyer WR, Eggleston JC. Bronchial carcinoid tumours. Cancer 1975;36:1522–1537.

    Article  CAS  PubMed  Google Scholar 

  368. Debelenko LV, Brambilla E, Agarwal SK, et al. Identification of MEN1 gene mutations in sporadic carcinoid tumours of the lung. Hum Mol Genet 1997;6:2285–2290.

    Article  CAS  PubMed  Google Scholar 

  369. Walch AK, Zitzelsberger HF, Aubele MM, et al. Typical and atypical carcinoid tumours of the lung are characterised by 11q deletions as detected by comparative genomic hybridisation. Am J Pathol 1998;153:1089–1098.

    CAS  PubMed  Google Scholar 

  370. Petzmann S, Ullmann R, Klemen H, et al. Loss of heterozygosity on chromosome arm 11q in lung carcinoids. Hum Pathol 2001;32:333–338.

    Article  CAS  PubMed  Google Scholar 

  371. Finkelstein SD, Hasegawa T, Colby T, et al. 11q13 allelic imbalance discriminates pulmonary carcinoids from tumourlets. A microdissection-based genotyping approach useful in clinical practice. Am J Pathol 1999;155:633–640.

    CAS  PubMed  Google Scholar 

  372. Matthews MJ, Gazdar AF. Small cell carcinoma of the lung. Its morphology, behaviour and nature. In: Shimosato Y, Melamed MR, Nettesheim P, eds. Morphogenesis of lung cancer. Vol 2. Boca Raton, FL: CRC Press, 1982:1–14.

    Google Scholar 

  373. Linnoila RI. Murine models for human lung neuroendocrine (NE) carcinomas: pathology and molecular determinants of differentiation. Lung Cancer 2003;41(suppl 2):3.

    Article  Google Scholar 

  374. Shapiro GI, Edwards CD, Kobzik L, et al. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. Cancer Res 1995;55:505–509.

    CAS  PubMed  Google Scholar 

  375. Beasley MB, Lantuejoul S, Abbondanzo S, et al. The P16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung. Hum Pathol 2003;34:136–142.

    Article  CAS  PubMed  Google Scholar 

  376. Wistuba II, Gazdar AF, Minna JD. Molecular genetics of small cell lung carcinoma. Semin Oncol 2001;28(suppl 4):3–13.

    Article  CAS  PubMed  Google Scholar 

  377. Minna JD, Kurie JM, Jacks T. A big step in the study of small cell lung cancer. Cancer Cell 2003;4:163–166.

    Article  CAS  PubMed  Google Scholar 

  378. Onuki N, Wistuba II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumours. Cancer 1999;85:600–607.

    Article  CAS  PubMed  Google Scholar 

  379. Debelenko LV, Swalwell JI, Kelley MJ, et al. MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma. Genes Chrom Cancer 2000;28:58–65.

    Article  CAS  PubMed  Google Scholar 

  380. Wistuba II, Berry J, Behrens C, et al. Molecular changes in the bronchial epithelium of patients with small cell lung cancer. Clin Cancer Res 2000;6:2604–2610.

    CAS  PubMed  Google Scholar 

  381. Mao L. Molecular abnormalities in lung carcinogenesis and their potential clinical implications. Lung Cancer 2001;34:S27–S34.

    Article  PubMed  Google Scholar 

  382. Brambilla E, Moro D, Gazzeri S, et al. Cytotoxic chemotherapy induces cell differentiation in small cell lung carcinoma. J Clin Oncol 1991;9:50–61.

    CAS  PubMed  Google Scholar 

  383. Mulshine JL, Smith RA. Screening and early diagnosis of lung cancer. Thorax 2002;57:1071–1078.

    Article  CAS  PubMed  Google Scholar 

  384. Strauss GM. Randomized population trials and screening for lung cancer. Cancer 2000;89:2399–2421.

    Article  CAS  PubMed  Google Scholar 

  385. Yoshida J, Nagai K, Yokose T, et al. Primary peripheral lung carcinoma smaller than 1 cm in diameter. Chest 1998;114:710–712.

    Article  CAS  PubMed  Google Scholar 

  386. Kerr KM, Lamb D. Actual growth rate and tumour cell proliferation in human pulmonary neoplasms. Br J Cancer 1984;50:343–349.

    CAS  PubMed  Google Scholar 

  387. Thunnissen FBJM. Sputum examination for early detection of lung cancer. J Clin Pathol 2003;56:805–810.

    Article  CAS  PubMed  Google Scholar 

  388. Hirsch FR, Franklin WA, Gazdar AF, et al. Early detection of lung cancer: clinical perspectives of recent advances in biology and radiology. Clin Cancer Res 2001;7:5–22.

    CAS  PubMed  Google Scholar 

  389. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early lung cancer action project: overall design and findings from baseline screening. Lancet 1999;354:99–105.

    Article  CAS  PubMed  Google Scholar 

  390. Kerr KM, Noguchi M. Pathology of Screen-detected lesions. In: Hirsch FR, Bunn PA, Kato JL, et al., eds. Prevention and early detection of lung cancer. London: IASLC/Martin Dunitz, 2005.

    Google Scholar 

  391. Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351:1242–1245.

    Article  CAS  PubMed  Google Scholar 

  392. Nawa T, Nakagawa T, Kusano S, et al. Lung cancer screening using low-dose spiral CT. Results of baseline and 1-year follow-up studies. Chest 2002;122:15–20.

    Article  PubMed  Google Scholar 

  393. Kodama K, Higashiyama M, Yokouchi H, et al. Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning. Lung Cancer 2001;33:17–25.

    Article  CAS  PubMed  Google Scholar 

  394. Nakata M, Sawada S, Saeki H, et al. Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography. Ann Thorac Surg 2003;75:1601–1605.

    Article  PubMed  Google Scholar 

  395. Takashima S, Maruyama Y, Hasegawa M, et al. Prognostic significance of high-resolution CT findings in small peripheral adenocarcinoma of the lung: a retrospective study on 64 patients. Lung Cancer 2002;36:289–295.

    Article  PubMed  Google Scholar 

  396. Flieder DB. Recent advances in the diagnosis of adenocarcinoma: the impact of lung cancer screening on histopathologists. Curr Diag Pathol 2004;10:269–278.

    Article  Google Scholar 

  397. Kennedy TC, Miller Y, Prindiville S. Screening for lung cancer revisited and the role of sputum cytology and fluorescence bronchoscopy in a high-risk group. Chest 2000;117:72S–79S.

    Article  CAS  PubMed  Google Scholar 

  398. McWilliams A, Mayo J, MacDonald S, et al. Lung cancer screening. A different paradigm. Am J Respir Crit Care Med 2003;168:1167–1173.

    Article  PubMed  Google Scholar 

  399. van Zandwijk N, Hirsch FR. Chemoprevention of lung cancer: current status and future prospects. Lung Cancer 2003;42:S71–S79.

    Article  PubMed  Google Scholar 

  400. Berman JJ, Henson DE. The precancers: Waiting for a classification. Hum Pathol 2003;34:833–834.

    Article  PubMed  Google Scholar 

  401. Foucar E. Do pathologists play dice? Uncertainty and early histopathological diagnosis of common malignancies. Histopathology 1997;31:495–502.

    Article  CAS  PubMed  Google Scholar 

  402. Page DL. Atypical Hyperplasia, narrowly and broadly defined. Hum Pathol 1991;22:631–632.

    Article  CAS  PubMed  Google Scholar 

  403. Banerjee AK, Rabbitts PH, George PJ. Preinvasive bronchial lesions. Surveillance or intervention? Chest 2004;125:95S–96S.

    Article  PubMed  Google Scholar 

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Kerr, K.M., Fraire, A.E. (2008). Preinvasive Disease. In: Tomashefski, J.F., Cagle, P.T., Farver, C.F., Fraire, A.E. (eds) Dail and Hammar’s Pulmonary Pathology. Springer, New York, NY. https://doi.org/10.1007/978-0-387-72114-9_3

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