Molecular Pathology of Squamous Cell Carcinoma and Its Precursors

  • Soon-Hee Jung
  • Bihong Zhao
  • Li Mao
  • Jae Y. Ro
Part of the Molecular Pathology Library book series (MPLB, volume 1)


The normal respiratory mucosal epithelium at birth may undergo histologic changes during life due to exposure to a variety of environmental irritants, including tobacco smoke, radon exposure, and occupational toxins. Long-term carcinogenic insults may result in the development of multiple premalignant or malignant lesions in the respiratory epithelium. There is a wide spectrum of histopathologic changes in the respiratory epithelium, including hyperplastic lesions (basal cell hyperplasia/reserve cell hyperplasia), metaplastic lesions (primarily squamous metaplasia), dysplasia (mild, moderate, and severe), squamous cell carcinoma in situ, and invasive squamous cell carcinoma.1 The precursor lesions are also described as preneoplastic, premalignant, or preinvasive and are defined as epithelial abnormalities that are cytologically neoplastic but do not penetrate the basement membrane.2 These lesions have the capacity to progress to invasive carcinoma, to regress toward normal, or to remain indolent.3


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


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kerr KM. Morphology and genetics of preinvasive pulmonary disease. Curr Diagn Pathol 2004;10:259–268.CrossRefGoogle Scholar
  2. 2.
    Travis WD, Colby TV, Corrin B, et al., eds. Histological Typing of Lung and Pleural Tumors. WHO International Histological Classification of Tumours, 3rd ed. Berlin: Springer; 1999.Google Scholar
  3. 3.
    Rocha AT, McCormack M, Montana G, Schreiber G. Association between lower lobe location and upstaging for earlystage non-small cell lung cancer. Chest 2004;25:1424–1430.CrossRefGoogle Scholar
  4. 4.
    Miller YE. Pathogenesis of lung cancer; 100 year report. Am J Respir Cell Mol Biol 2005;3:216–223.CrossRefGoogle Scholar
  5. 5.
    Hirsch FR, Franklin WA, Gazdar AF, Bunn Jr PA. Early detection of lung cancer: clinical perspectives of recent advances in biology and radiology. Clin Cancer Res 2001;7:5–22.PubMedGoogle Scholar
  6. 6.
    Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 2003;3:1727–1730.Google Scholar
  7. 7.
    Yokota J, Takashi K. Molecular footprints of human lung cancer progression. Cancer Sci 2004;95:197–204.CrossRefPubMedGoogle Scholar
  8. 8.
    Rom WN, Tchou-Wong KM. Molecular and genetic aspects of lung cancer. Methods Mol Med 2003;75:3–26.PubMedGoogle Scholar
  9. 9.
    Wistuba II, Gazdar AF. Characteristic genetic alterations in lung cancer. In: Driscoll B, ed. Lung Cancer: Molecular Pathology Methods and Reviews, vol 1. Los Angeles: Humana Press; 2003:3–28.Google Scholar
  10. 10.
    Forgacs E, Zochbauer-Muller S, Olah E, Minna JD. Molecular genetic abnormalities in the pathogenesis of human lung cancer. Pathol Oncol Res 2001;7(1):6–13.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefPubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Chung GTY, Sundaresan V, Hasleton P, et al. Clonal evolution of lung tumors. Cancer Res 1996;56:1609–1614.PubMedGoogle Scholar
  14. 14.
    Thiberville L, Payne P, Vielkinds J, et al. Evidence of cumulative losses with progression of premalignant epithelial lesions to carcinoma of the bronchus. Cancer Res 1995;55:5133–5139.PubMedGoogle Scholar
  15. 15.
    Zavorovsky ER, Lerman MI, Minna JD. Chromosome 3 abnormalities in lung cancer. In Pass HI, Carbone DP, Johnson DH, et al, eds. Lung Cancer, 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2005:118–134.Google Scholar
  16. 16.
    Gazdar AF, Bader S, Hung J, et al. Molecular genetic changes found in human lung cancer and its precursor lesions. Cold Spring Harb Symp Quant Biol 1994;109:565–572.Google Scholar
  17. 17.
    Vincenzi B, Schiavon G, Silletta M, et al. Cell cycle alterations and lung cancer. Histol Histopathol 2006;21:423–435.PubMedGoogle Scholar
  18. 18.
    Greenblatt MS, Benett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994;54:4855–4878.PubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    Harris CC. p53 tumor suppressor gene: from the basic research laboratory to the clinic—an abridged historical perspective. Carcinogenesis 1996;17:1187–1198.CrossRefPubMedGoogle Scholar
  21. 21.
    Ramet M, Casten K, Jarvinen K, et al. p53 protein expression is correlated with benzo[a]pyrene-DNA adducts in carcinoma cell lines. Carcinogenesis 1996;16:2117–2124.CrossRefGoogle Scholar
  22. 22.
    Pfeifer GP, Denissenko MF, Olivier M, et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 2002;21:7435–7451.CrossRefPubMedGoogle Scholar
  23. 23.
    Bennett WP, Colby TV, Travis WD, et al. p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res 1993;53:4817–4822.PubMedGoogle Scholar
  24. 24.
    Gorgoulis VG, Zacharatos P, Kotsinas A, et al. Alterations of the p16-pRb pathway and the chromosome locus 9p21–22 in non-small-cell lung carcinomas. Relationship with p53 and MDM2 protein expression. Am J Pathol 1998;153:1749–1765.PubMedGoogle Scholar
  25. 25.
    Bates S, Phillips AC, Clark PA, et al. p14ARF links the tumour suppressors RB and p53. Nature 1998;395:124–125.CrossRefPubMedGoogle Scholar
  26. 26.
    Zochbauer-Muller S, Lam S, Toyooka S, et al. Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers. Int J Cancer 2003;107:612–616.CrossRefPubMedGoogle Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    Brambilla E, Moro D, Gazzeri S, Brambilla C. 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.CrossRefPubMedGoogle Scholar
  29. 29.
    Park MJ, Shimizu K, Nakano T, et al. Pathogenetic and biologic significance of TP14ARF alterations in nonsmall cell lung carcinoma. Cancer Genet Cytogenet 2003;141:5–13.CrossRefPubMedGoogle Scholar
  30. 30.
    Gazzeri S, Gouyer V, Vour’ch C, et al. Mechanisms of p16INK4A inactivation in non small-cell lung cancers. Oncogene 1998;16:497–504.CrossRefPubMedGoogle Scholar
  31. 31.
    Sato M, Horio Y, Sekido Y, et al. The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14(ARF), p16(INK4a) and RASSF1A in human lung cancer cell lines. Oncogene 2002;21:4822–4829.CrossRefPubMedGoogle Scholar
  32. 32.
    Bates S, Phillips AC, Clark PA, et al. p14ARF links the tumour suppressors RB and p53. Nature 1998;395:124–125.CrossRefPubMedGoogle Scholar
  33. 33.
    Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphates gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943–1947.CrossRefPubMedGoogle Scholar
  34. 34.
    Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997;15:356–362.CrossRefPubMedGoogle Scholar
  35. 35.
    Weng L, Brown J, Eng C. PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Aktdependent degradation and-independent pathways. Hum Mol Genet 200;10:237–242.CrossRefGoogle Scholar
  36. 36.
    Mamllapalli R, Gavrilova N, Mihaykiva VT, et al. PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2). Curr Biol 2001;11:23–27.Google Scholar
  37. 37.
    Tamura M, Gu J, Matsumoto K, et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 1998;280:1614–1617.CrossRefPubMedGoogle Scholar
  38. 38.
    Forgacs E, Biesterveld EJ, Sekido Y, et al. Mutation analysis of the PTEN/MMAC1 gene in lung cancer. Oncogene 1998;17:1557–1565.CrossRefPubMedGoogle Scholar
  39. 39.
    Petersen S, Rudolf J, Bockmuhl U, et al. Distinct regions of allelic imbalance on chromosome 10q22–q26 in squamous cell carcinomas of the lung. Oncogene 1998;17:449–454.CrossRefPubMedGoogle Scholar
  40. 40.
    Marsit CJ, Zheng S, Aldape K, et al. PTEN expression in non-small cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 2005;36:768–776.CrossRefPubMedGoogle Scholar
  41. 41.
    de Lange T. Activation of telomerase in a human tumor. Proc Natl Acad Sci USA 1994;91:2882–2885.CrossRefPubMedGoogle Scholar
  42. 42.
    Harley CB, Villeponteau B. Telomere and telomerase in aging and cancer. Curr Opin Genet Dev 1995;5:249–255.CrossRefPubMedGoogle Scholar
  43. 43.
    Kiyono T, Foster SA, Koop JI, et al. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 1998;396:84–88.CrossRefPubMedGoogle Scholar
  44. 44.
    Chin L, Artandi SE, Shen Q, et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 1999;97:527–538.CrossRefPubMedGoogle Scholar
  45. 45.
    Hiyama K, Hiyama E, Ishioka S, et al. Telomerase activity in small-cell and non-small-cell lung cancers. J Natal Cancer Inst 1995;87:895–902.CrossRefGoogle Scholar
  46. 46.
    Albanell J, Lonardo F, Rusch V, et al. High telomerase activity in primary lung cancers: association with increased cell proliferation rates and advanced pathologic stage. J Natl Cancer Inst 1997;89:1609–1615.CrossRefPubMedGoogle Scholar
  47. 47.
    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.PubMedGoogle Scholar
  48. 48.
    Lantuejoul S, Soria JC, Morat L, et al. Telemerase shortening and telomerase reverse transcriptase expression in preinvasive bronchial lesions. Clin Cancer Res 2005;11:2074–2082.CrossRefPubMedGoogle Scholar
  49. 49.
    Miyazu YM, Miyazawa T, Hiyama K, et al. Telomerase expression in noncancerous bronchial epithelia is a possible marker of early development of lung cancer. Cancer Res 2005;65:9623–9627.CrossRefPubMedGoogle Scholar
  50. 50.
    Mills NE, Fishman CL, Rom WN, et al. Increased prevalence of K-ras oncogene mutations in lung adenocarcinoma. Cancer Res 1995;55:1444–1447.PubMedGoogle Scholar
  51. 51.
    Viallet J, Minna J. Dominant oncogenes and tumor suppressor genes in the pathogenesis of human lung cancer. Am J Respir Cell Mol Biol 1990;2:225–232.PubMedGoogle Scholar
  52. 52.
    Kern JA, Robinson RA, Gazdar AF, et al. Mechanisms of p185HER2 expression in human non-small cell lung cancer cell lines. Am J Respir Cell Mol Biol 1992;6:359–363.PubMedGoogle Scholar
  53. 53.
    Pazzella F, Turley H, Kuzu I, et al. bcl-2 protein in non-small cell lung carcinoma. N Engl J Med 1993;329:690–694.CrossRefGoogle Scholar
  54. 54.
    Walker C, Robertson L, Myskow M, Dixon G. Expression of the BCL-2 protein in normal and dysplastic bronchial epithelium and in lung carcinomas. Br J Cancer 1995;72:164–169.PubMedGoogle Scholar
  55. 55.
    Uren AG, Vaux DL. Molecular and clinical aspects of apoptosis. Pharmacol Ther 1996;72:37–50.CrossRefPubMedGoogle Scholar
  56. 56.
    Marchetti A, Buttitta F, Pellegrini S, et al. mdm2 gene amplification and overexpression in non-small cell lung carcinomas with accumulation of the p53 protein in the absence of p53 gene mutations. Diagn Mol Pathol 1995;4:93–97.CrossRefPubMedGoogle Scholar
  57. 57.
    Cole SP, Bhardwaj G, Gerlach JH, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992;258:1650–1654.CrossRefPubMedGoogle Scholar
  58. 58.
    Eijdems EW, De Haas M, Coco-Martin JM, et al. Mechanisms of MRP overexpression in four human lung cancer cell lines and analysis of the MRP amplicon. Int J Cancer 1995;60:676–684.CrossRefPubMedGoogle Scholar
  59. 59.
    Ray ME, Guan XY, Slovak ML, et al. Rapid detection, cloning and molecular cytogenetic characterization of sequences from an MRP-encoding amplicon by chromosome microdissection. Br J Cancer 1994;70:85–90.PubMedGoogle Scholar
  60. 60.
    Brunn PA Jr, Franklin W. Epidermal growth factor receptor expression, signal pathway, and inhibitors in non-small cell lung cancer. Semin Oncol 2002;29:38–44.Google Scholar
  61. 61.
    Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149–2158.CrossRefPubMedGoogle Scholar
  62. 62.
    Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339–346.PubMedGoogle Scholar
  63. 63.
    Cohen MH, Williams GA, Sridhara R, et al. United States Food and Drug Administration drug approval summary: gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res 2004;10:1212–1218.CrossRefPubMedGoogle Scholar
  64. 64.
    Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.CrossRefPubMedGoogle Scholar
  65. 65.
    Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.CrossRefPubMedGoogle Scholar
  66. 66.
    Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers“ and are associated with sensitivity of tumor to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004;101:13306–13311CrossRefPubMedGoogle Scholar
  67. 67.
    Borczuk AC, Gorenstein L, Walter K, et al. Non-small cell lung cancer molecular signatures recapitulate lung developmental pathways. Am J Pathol 2003;163:1949–1960.PubMedGoogle Scholar
  68. 68.
    Jeon YK, Sung SW, Chung J-H, et al. Clinicopathologic features and prognostic implications of epidermal growth factor receptor (EGFR) gene copy number and protein expression in non-small cell lung cancer. Lung Cancer 2006;54:387–398CrossRefPubMedGoogle Scholar
  69. 69.
    Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 2005;353:123–132.CrossRefPubMedGoogle Scholar
  70. 70.
    Tsao M-S, Sakurada A, Cutz J-C, et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144.CrossRefPubMedGoogle Scholar
  71. 71.
    Cappuzzo F, Magrini E, Ceresoli GL, et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small cell lung cancer. J Natl Cancer Inst 2004;96:1133–1141.PubMedCrossRefGoogle Scholar
  72. 72.
    Suzuki S, Igarashi S, Hanawa M, et al. Diversity of epidermal growth factor receptor-mediated activation of downstream molecules in human lung carcinomas. Mod Pathol 2006;28:1–13.Google Scholar
  73. 73.
    Hirsh F, Scagliotti GV, Langer CJ, et al. Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. Lung Cancer 2003;41:S29.CrossRefGoogle Scholar
  74. 74.
    Kosaka T, Yatabe Y, Endoh H, et al. Mutations of the epidermal growth factor receptor gene in lung cancer. Biological and clinical implications. Cancer Res 2004;64:8919–8923.CrossRefPubMedGoogle Scholar
  75. 75.
    Reissmann PT, Koga H, Figlin RA, et al. Amplification and overexpression of the cyclin D1 and epidermal growth factor receptor genes in non-small cell lung cancer. J Cancer Res Clin Oncol 2004;125:61–70.CrossRefGoogle Scholar
  76. 76.
    Kelly MJ, Linnoila RI, Avis IL, et al. Antitumor activity of a monoclonal antibody directed against gastrin-releasing peptide in patients with small cell lung cancer. Chest 1997;112:256–261.CrossRefGoogle Scholar
  77. 77.
    Aguayo SM, Kane MA, King TE Jr, et al. Increased levels of bombesin-like peptides in the lower respiratory tract of asymptomatic cigarette smokers. J Clin Invest 1989;84:1105–1113.CrossRefPubMedGoogle Scholar
  78. 78.
    Aguayo SM, King TE Jr, Kane MA, et al. Urinary levels of bombesin-like peptides in asymptomatic cigarette smoker: a potential risk marker for smoking-related diseases. Cancer Res 1992;52:2727s–2731s.PubMedGoogle Scholar
  79. 79.
    Chan D, Gera L, Stewart J, et al. Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a “biased agonist” mechanism. Proc Natl Acad Sci USA 2002;99:4608–4613CrossRefPubMedGoogle Scholar
  80. 80.
    Strieter RM, Belperio JA, Burdick MD, et al. CXC chemokines: angiogenesis, immunoangiostasis, and metastases in lung cancer. Ann NY Acad Sci 2004;1078:351–360.CrossRefGoogle Scholar
  81. 81.
    Sutedja G. New techniques for early detection of lung cancer. Eur Respir J 2003;21:57s–66s.CrossRefGoogle Scholar
  82. 82.
    Miura N, Nakamura H, Sato R, et al. Clinical usefulness of serum telomerase reverse transcriptase (hTERT) mRNA and epidermal growth factor receptor (EGFR) mRNA as a novel tumor marker for lung cancer. Cancer Science 2006;97:1366–1373.CrossRefPubMedGoogle Scholar
  83. 83.
    Merrick DT, Kittelson J, Winterhalder R, et al. Analysis of cErbB1/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;12:2281–2288.CrossRefPubMedGoogle Scholar
  84. 84.
    Mathur PN, Edell E, Sutedja T, et al. Treatment of early stage non-small cell lung cancer. Chest 2003;123:176–180.CrossRefGoogle Scholar
  85. 85.
    Koike T, Terashima M, Takizawa T, et al. Surgical results for centrally-located early stage lung cancer. Ann Thorac Surg 2000;70:1176–1179.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Soon-Hee Jung
    • 1
  • Bihong Zhao
    • 2
  • Li Mao
    • 3
  • Jae Y. Ro
    • 4
  1. 1.Department of PathologyYonsei University/Wonju Christian HospitalWonju, Kangwon-DoKorea
  2. 2.Department of Pathology, Methodist Hospital, Weill Medical CollegeCornell UniversityHoustonUSA
  3. 3.Department of Thoracic and Head and Neck Medical OncologyUniversity of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Department of PathologyCornell University/Methodist Hospital and University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations