Current Oncology Reports

, Volume 8, Issue 2, pp 146–154 | Cite as

Oral premalignancy: New methods of detection and treatment

  • Ann Gillenwater
  • Vali Papadimitrakopoulou
  • Rebecca Richards-Kortum


Oral carcinogenesis proceeds through a stepwise accumulation of genetic damage over time. Because the oral cavity is easy to examine and risk factors for oral cancer are known, there is great opportunity to improve patient outcomes through diagnosis and treatment of premalignant lesions before the development of invasive oral carcinoma. This review provides a summary of developments in detection and diagnosis of oral premalignant lesions and innovative approaches to management of early oral neoplasia. These technological and therapeutic advances are much needed to improve the poor outcomes associated with oral cancer due to our inability to diagnose and treat this disease at an early, curable stage.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Vogelstein B, Kinzler KW: The multistep nature of cancer trends. Genet (England) 1993, 9:38–41.Google Scholar
  2. 2.
    Califano J, van der Riet P, Westra W, et al.: Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 1996, 56:2488–2492.PubMedGoogle Scholar
  3. 3.
    Braakhuis BJM, Leemans CR, Brakenhoff RH: A genetic progression model of oral cancer: current evidence and clinical implications. J Oral Pathol Med 2004, 33:317–322. An excellent, thoughtful review of current knowledge on the molecular progression associated with oral carcinogenesis and the potential role of a genetically altered stem cell population.PubMedCrossRefGoogle Scholar
  4. 4.
    Lippman SM, Hong WK: Molecular markers of the risk of oral cancer. N Engl J Med 2001, 344:1323–1326.PubMedCrossRefGoogle Scholar
  5. 5.
    Lippman SM, Sudbo J, Hong WK: Oral cancer prevention and the evolution of molecular-targeted drug development. J Clin Oncol 2005, 23:346–356.PubMedCrossRefGoogle Scholar
  6. 6.
    Banerjee AG, Bhattacharyya I, Vishwanatha JK: Identification of genes and molecular pathways involved in the progression of premalignant oral epithelia. Mol Cancer Ther 2005, 4:865–875.PubMedCrossRefGoogle Scholar
  7. 7.
    Slaughter OP: Multicentric origin of intraoral carcinoma. Surgery 1946, 20:133–146. This report, along with that of Strong et al. [8], are the classic descriptions leading to the acceptance of the concept of "field cancerization" and "field effect" in oral and head and neck carcinogenesis.Google Scholar
  8. 8.
    Strong MS, Incze J, Vaughan CN: Field cancerization in the aerodigestive tract — its etiology, manifestation, and significance. J Otolaryngol 1984, 13:1–6. This report, along with that of Slaughter et al. [7], are the classic descriptions leading to the acceptance of the concept of "field cancerization" and "field effect" in oral and head and neck carcinogenesis.PubMedGoogle Scholar
  9. 9.
    Incze J, Vaughan CW Jr, Lui P, et al.: Premalignant changes in normal appearing epithelium in patients with squamous cell carcinoma of the upper aerodigestive tract. Am J Surg 1982, 144:401–405.PubMedCrossRefGoogle Scholar
  10. 10.
    Westra WH, Sidransky D: Phenotypic and genotypic disparity in premalignant lesions: of calm water and crocodiles. J Natl Cancer Inst 1998, 90:1500–1501.PubMedCrossRefGoogle Scholar
  11. 11.
    Reibel J: Prognosis of oral pre-malignant lesions: significance for clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 2003, 14(1):47–62.PubMedGoogle Scholar
  12. 12.
    Silverman S, Gorsky M, Lozada F: Oral leukoplakia and malignant transformation: a follow-up study of 257 patients. Cancer 1984, 53:563–568. This is a classic description of patients with oral leukoplakia documenting the clinical follow-up over time and the development of oral carcinoma.PubMedCrossRefGoogle Scholar
  13. 13.
    Reichart PA, Philipsen HP: Oral erythroplakia: a review. Oral Oncol 2005, 41:551–561.PubMedCrossRefGoogle Scholar
  14. 14.
    Axell T, Pindborg JJ, Smith CJ, van der Waal I: Oral white lesions with special reference to precancerous and tobacco-related lesions: conclusions of an international symposium held in Uppsala, Sweden, May 18–21 1994. International Collaborative Group on Oral White Lesions. J Oral Pathol Med 1996, 25:49–54.PubMedCrossRefGoogle Scholar
  15. 15.
    Van der Waal I, Schepman KP, van der Meij EH: A modified classification and staging system for oral leukoplakia. Oral Oncol 2000, 36:264–266. This report describes the staging system frequently cited for use in oral leukoplakia patients.PubMedCrossRefGoogle Scholar
  16. 16.
    Scully C, Sudbo J, Speight PM: Progress in determining the malignant potential of oral lesions. J Oral Pathol Med 2003, 32:251–256.PubMedGoogle Scholar
  17. 17.
    Sudbo J, Kildal W, Risberg B, et al.: DNA content as a prognostic marker in patients with oral leukoplakia. N Engl J Med 2001, 344:1270–1278.PubMedCrossRefGoogle Scholar
  18. 18.
    Lee JJ, Hong WK, Hittelman WN, et al.: Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res 2000, 6:1702–1710.PubMedGoogle Scholar
  19. 19.
    Lam S, MacAulayC, leRiche JC, Palcic B: Detection and localization of early lung cancer by fluorescence bronchoscopy. Cancer, 2000 (89 Suppl):2468–2473.Google Scholar
  20. 20.
    Stanzel F: Fluorescent bronchoscopy: contribution for lung cancer screening? Lung Cancer, 2004 (Suppl 45): S29–S37.Google Scholar
  21. 21.
    Bogaards A, Varma A, Zhang K, et al.: Fluorescence imageguided brain tumor resection with adjuvant metronomic photodynamic therapy: pre-clinical model and technology development. Photochem Photobiol Sci 2005, 4:438–442.PubMedCrossRefGoogle Scholar
  22. 22.
    Kara MA, Smits ME, Rosmolen WD, et al.: A randomized crossover study comparing light-induced fluorescence endoscopy with standard videoendoscopy for the detection of early neoplasia in Barrett’s esophagus. Gastrointest Endosc 2005, 61:671–678.PubMedCrossRefGoogle Scholar
  23. 23.
    Kulapaditharom B, Boonkitticharoen V: Laser-induced fluorescence imaging in localization of head and neck cancers. Ann Otol Rhinol Laryngol 1998, 107:241–246.PubMedGoogle Scholar
  24. 24.
    Onizawa K, Saginoya H, Furuya Y, et al.: Usefulness of fluorescence photography for diagnosis of oral cancer. Int J Oral Maxillofac Surg 1999, 28:206–210.PubMedCrossRefGoogle Scholar
  25. 25.
    Svistun E, Alizadeh-Naderi R, El-Naggar A, et al.: Vision enhancement system for detection or oral cavity neoplasia based on autofluorescence. Head Neck 2004, 26:205–215.PubMedCrossRefGoogle Scholar
  26. 26.
    Wagnieres GA, Star WM, Wilson BC: In vivo fluorescence spectroscopy and imaging for oncological applications. Photochem Photobiol 1998, 68:603–632.PubMedCrossRefGoogle Scholar
  27. 27.
    Ramanujam N: Fluorescence spectroscopy of neoplastic and non-neoplastic tissues. Neoplasia 2000, 2:89–117. An excellent overview of principles behind fluorescence spectroscopy and some potential clinical applications of this technology.PubMedCrossRefGoogle Scholar
  28. 28.
    Schantz SP, Kolli V, Savage HE, et al.: In vivo native cellular fluorescence and histological characteristics of head and neck cancer. Clin Cancer Res 1998, 4:1177–1182.PubMedGoogle Scholar
  29. 29.
    Dhingra JK, Perrault DF Jr, McMillan K, et al.: Early diagnosis of upper aerodigestive tract cancer by autofluorescence. Arch Otolaryngol Head Neck Surg 1996, 122:1181–1186.PubMedGoogle Scholar
  30. 30.
    Gillenwater AM, Jacob R, Ganeshappa R, et al.: Noninvasive diagnosis of oral neoplasia based on fluorescence spectroscopy and native tissue autofluorescence. Arch Otolaryngol Head Neck Surg 1998, 124:1251–1258.PubMedGoogle Scholar
  31. 31.
    Heintzelman D, Utzinger U, Fuchs H, et al.: Optimal excitation wavelengths for in vivo detection of oral neoplasia using fluorescence spectroscopy. Photochem Photobiol 2000, 72:103–113.PubMedCrossRefGoogle Scholar
  32. 32.
    Sokolov K, Drezek R, Gossage K, Richards-Kortum R: Reflectance spectroscopy with polarized light: is it sensitive to cellular and nuclear morphology? Opt Expr 1999, 5:302–317.CrossRefGoogle Scholar
  33. 33.
    Gurjar RS, Backman V, Perelman LT, et al.: Imaging human epithelial properties with polarized light-scattering spectroscopy. Nat Med 2001, 7:1245–1248.PubMedCrossRefGoogle Scholar
  34. 34.
    Muller MG, Valdez TA, Georgakoudi I, et al.: Spectroscopic detection and evaluation of morphologic and biochemical changes in early human oral carcinoma. Cancer 2003, 97:1681–1692.PubMedCrossRefGoogle Scholar
  35. 35.
    Georgakoudi I, Jacobson BC, Van Dan J, et al.: Fluorescence, reflectance, and light-scattering spectroscopy for evaluating dysplasia in patients with Barrett’s esophagus. Gastroenterology 2001, 120:1620–1629.PubMedCrossRefGoogle Scholar
  36. 36.
    Chang SK, Mirabal YN, Atkinson EN, et al.: Combined reflectance and fluorescence spectroscopy for in vivo detection of cervical pre-cancer. J Biomed Opt 2005, 10:024–031.CrossRefGoogle Scholar
  37. 37.
    Rosenberg D, Cretin S: Use of meta-analysis to evaluate tolonium chloride in oral cancer screening. Oral Surg Oral Med Oral Pathol 1987, 67:621–627.CrossRefGoogle Scholar
  38. 38.
    Epstein JB, Scully C, Spinelli JJ: Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Pathol Med 1992, 21:160–163.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang L, Williams M, Poh CF, et al.: Toluidine blue staining identifies high-risk primary oral premalignant lesions with poor outcome. Cancer Res 2005, 65:8017–8021.PubMedGoogle Scholar
  40. 40.
    Leunig A, Betz CS, Mehlmann M, et al.: Detection of squamous cell carcinoma of the oral cavity by imaging 5-aminolevulinic acid-induced protoporphyrin IX fluorescence. Laryngoscope 2000, 1100:78–83.CrossRefGoogle Scholar
  41. 41.
    Zheng W, Olivo M, Soo KC: The use of digitized endoscopic imaging of 5-ALA-induced PPIX fluorescence to detect and diagnose oral premalignant and malignant lesions in vivo. Int J Cancer 2004, 110:295–300.PubMedCrossRefGoogle Scholar
  42. 42.
    Huber MA, Bsoul SA, Terezhalmy GT: Acetic acid wash and chemiluminescent illumination as an adjunct to conventional oral soft tissue examination for the detection of dysplasia: pilot study. Quintessence Int 2004, 35:378–384.PubMedGoogle Scholar
  43. 43.
    Sokolov K, Aaron J, Hsu B, et al.: Optical systems for in vivo molecular imaging of cancer. Technol Cancer Res Treat 2003, 2:491–504.PubMedGoogle Scholar
  44. 44.
    Soukos NS, Hamblin MR, Keel S, et al.: Epidermal growth factor receptor-targeted immunophotodiagnosis and photoimmunotherapy of oral precancer in vivo. Cancer Res 2001, 61:4490–4496.PubMedGoogle Scholar
  45. 45.
    Hsu ER, Anslyn EV, Dharmawardhane S, et al.: A far-red fluorescent contrast agent to image epidermal growth factor receptor expression. Photochem Photobiol 2004, 79:272–279.PubMedCrossRefGoogle Scholar
  46. 46.
    Sokolov K, Follen M, Aaron J, et al.: Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanoparticles. Cancer Res 2003, 63:1999–2004.PubMedGoogle Scholar
  47. 47.
    El-Sayed IH, Huang X, El-Sayed AM: Surface plasmon resonance scattering and absorption of anti-EGF antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer. Nano Lett 2005, 5:829–834.PubMedCrossRefGoogle Scholar
  48. 48.
    Sciubba JJ: Improving detection of precancerous and cancerous oral lesions. Computer-assisted analysis of the oral brush biopsy. U.S. Collaborative OralCDx Study Group. J Am Dent Assoc 1999, 130:1445–2457. This paper reports the findings of a large multicenter trial conducted by academic dental specialists evaluating the efficacy of the OralCDx brush biopsy for noninvasive diagnosis of oral lesions. Surgical biopsies were only performed when the brush biopsy was atypical or positive; therefore, there is no way to document whether there were any false-negative results.PubMedGoogle Scholar
  49. 49.
    Poate TWJ, Buchanan JAG, Hodgson TA, et al.: An audit of the efficacy of the oral brush biopsy technique in a specialist Oral Medicine unit. Oral Oncol 2004, 40:829–834. An important study documenting the sensitivity, specificity, and positive and negative predictive ability of the OralCDx brush biopsy.PubMedCrossRefGoogle Scholar
  50. 50.
    Potter TJ, Summerlin D-J, Campbell JH: Oral malignancies associated with negative transepithelial brush biopsy. J Oral Maxillofac Surg 2003, 61:674–677.PubMedCrossRefGoogle Scholar
  51. 51.
    Clark AL, Gillenwater AM, Collier TC, et al.: Confocal microscopy for real-time detection of oral cavity neoplasia. Clin Cancer Res 2003, 9:4714–4721.PubMedGoogle Scholar
  52. 52.
    Colston BW Jr, Everett MJ, Sathyam US, et al.: Imaging of the oral cavity using optical coherence tomography. Mogr Oral Sci 2000, 17:32–55.CrossRefGoogle Scholar
  53. 53.
    Wilder-Smith, Jung WG, Brenner M, et al.: In vivo optical coherence tomography for the diagnosis of oral malignancy. Laser Surg Med 2004, 35:269–275.CrossRefGoogle Scholar
  54. 54.
    Li Y, St. John MAR, Zhou X, et al.: Salivary transcriptome diagnostics for oral cancer detection. Clin Cancer Res 2004, 10:8442–8450.PubMedCrossRefGoogle Scholar
  55. 55.
    El-Naggar AK, Mao L, Staerkel G, et al.: Genetic heterogeneity in saliva from patients with oral squamous carcinomas: implications in molecular diagnosis and screening. J Mol Diagn 2001, 3:164–170.PubMedGoogle Scholar
  56. 56.
    Spafford MF, Koch WM, Reed AL, et al.: Detection of head and neck squamous cell carcinoma among exfoliated oral mucosal cells by microsatellite analysis. Clin Cancer Res 2001, 7:607–612.PubMedGoogle Scholar
  57. 57.
    Tradati N, Grigolat R, Calabrese L, et al.: Oral leukoplakias: to treat or not? Oral Oncol 1997, 33:317–321.PubMedCrossRefGoogle Scholar
  58. 58.
    Van der Hem PS, Nauta JM, van der Wal JE, Roodenburg JLN: The results of CO2 laser surgery in patients with oral leukoplakia: a 25 year follow up. Oral Oncol 2005, 41:31–37.PubMedCrossRefGoogle Scholar
  59. 59.
    Vedtofte P, Holmstrup P, Hjorting-Hansen E, Pindborg JJ: Surgical treatment of premalignant lesions of the oral mucosa. Int J Oral Maxillofac Surg 1987, 16:656–664.PubMedCrossRefGoogle Scholar
  60. 60.
    Sudbo J, Lippman SM, Lee JJ, et al.: The influence of resection and aneuploidy on mortality in oral leukoplakia. N Engl J Med 2004, 350:1405–1413. An important paper documenting the impact of aneuploidy in oral leukoplakic lesions on patient survival rates after subsequent oral cancer development in a high-risk population in Norway.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang L, Poh CF, Lam WL, et al.: Impact of localized treatment in reducing risk of progression of low-grade oral dysplasia: Molecular evidence of incomplete resection. Oral Oncol 2001, 37:505–512.PubMedCrossRefGoogle Scholar
  62. 62.
    Dolmans DEJGJ, Fukumura D, Jain RK: Photodynamic therapy for cancer. Nat Rev Cancer 2003, 3:380–386.PubMedCrossRefGoogle Scholar
  63. 63.
    Kubler A, Haase T, Rheinwald M, et al.: Treatment of oral leukoplakia by topical application of 5-aminolevulinic acid. Int J Oral Maxillofac Surg 1998, 27:466–469.PubMedCrossRefGoogle Scholar
  64. 64.
    Fan KF, Hopper C, Speight PM, et al.: Photodynamic therapy using 5-aminolevulinic acid for premalignant and malignant lesions of the oral cavity. Cancer 1996, 78:1374–1383.PubMedCrossRefGoogle Scholar
  65. 65.
    Sieron A, Adamek M, Kawczyk-Krupka A, et al.: Photodynamic therapy (PDT) using topically applied g-aminolevulinic acid (ALA) for the treatment of oral leukoplakia. J Oral Pathol Med 2003, 32:330–336.PubMedCrossRefGoogle Scholar
  66. 66.
    Hong WK, Endicott J, Itri LM, et al.: 13-cis retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986, 315:1501–1505. This landmark paper documented the first prospective, randomized, placebo-controlled trial showing efficacy of chemoprevention to reverse premalignant changes in oral mucosa.PubMedCrossRefGoogle Scholar
  67. 67.
    Lippman SM, Bastsakis JG, Toth BB, et al.: Comparison of low-dose isoretinoin therapy with beta carotene to prevent oral carcinogenesis. N Engl J Med 1993, 328:15–20.PubMedCrossRefGoogle Scholar
  68. 68.
    Papadimitrikopoulou VA, Hong WK, Lee JS, et al.: Low dose isoretinoin versus beta carotene to prevent oral carcinogenesis: long term follow up. J Natl Cancer Inst 1997, 89:257–258.CrossRefGoogle Scholar
  69. 69.
    Chiesa F, Tradati N, Marazza M, et al.: Fenretinide (4-HPR) in chemoprevention of oral leukoplakia. J Cell Biochem Suppl 1993, 17F:255–261.PubMedCrossRefGoogle Scholar
  70. 70.
    Mao L, El-Naggar AK, Papadmitrakopoulou V, et al.: Phenotype and genotype of advanced premalignant head and neck lesions after chemopreventive therapy. J Natl Cancer Inst 1998, 90:1545–1551.PubMedCrossRefGoogle Scholar
  71. 71.
    Benner SE, Winn RJ, Lippman SM, et al.: Regression of oral leukoplakia with alpha-tocopherol: a community clinical oncology program chemoprevention study. J Natl Cancer Inst 1993, 85:44–47.PubMedCrossRefGoogle Scholar
  72. 72.
    Armstrong WB, Kennedy AR, Wan XS, et al.: Clinical modulation of oral leukoplakia and protease activity by Bowman-Birk inhibitor concentrate in a phase IIa chemoprevention trial. Clin Cancer Res 2000, 6:4684–4691.PubMedGoogle Scholar
  73. 73.
    Cheng AL, Hsu CH, Lin JK, et al.: Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001, 21:2895–2900.PubMedGoogle Scholar
  74. 74.
    Rudin CM, Cohen EEX, Papdimitrakopoulou VA, et al.: An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia. J Clin Oncol 2003, 21:4546–4552.PubMedCrossRefGoogle Scholar
  75. 75.
    Papadimitrakopoulou VA: Chemoprevention of head and neck cancer: an update. Curr Opin Oncol 2002, 14:318–322. A good review of recent chemoprevention trials.PubMedCrossRefGoogle Scholar
  76. 76.
    Rhee JC, Khuri FR, Shin DM: Advances in chemoprevention of head and neck cancer. Oncologist 2004, 9:302–311. A good review of recent chemoprevention trials.PubMedCrossRefGoogle Scholar
  77. 77.
    Wang Z: The role of COX-2 in oral cancer development, and chemoprevention/treatment of oral cancer by selective COX-2 inhibitors. Curr Pharm Des 2005, 11:1771–1777.PubMedCrossRefGoogle Scholar
  78. 78.
    Lippman SM, Gibson N, Subbaramaiah K, Dannenberg AJ: Combined targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways. Clin Cancer Res 2005, 11:6097–6099.PubMedCrossRefGoogle Scholar
  79. 79.
    Chan G, Boyle JO, Yang EK, et al.: Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res 1999, 59:991–994.PubMedGoogle Scholar
  80. 80.
    Nishimura N, Manno Y, Takaoka K, et al.: Increased expression of cyclooxygenase (COX)-2 in DMBA-induced hamster cheek pouch carcinogenesis and chemopreventive effect of a selective COX-2 inhibitor celecoxib. J Oral Pathol Med 2004, 33:614–621.PubMedCrossRefGoogle Scholar
  81. 81.
    Mulshine JL, Atkinson JC, Greer RO, et al.: Randomized, double-blind, placebo-controlled phase IIb trial of the cyclooxygenase inhibitor ketorolac as an oral rinse in oropharyngeal leukoplakia. Clin Cancer Res 2004, 10:1565–1573.PubMedCrossRefGoogle Scholar
  82. 82.
    Shin DM, Ro JY, Hong WK, Hittleman WN: Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 1994, 54:3153–3159.PubMedGoogle Scholar
  83. 83.
    Dassonville O, Formento JL, Francoual M, et al.: Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 1993, 11:1873–1878.PubMedGoogle Scholar
  84. 84.
    Pomerantz RG, Grandis JR: The epidermal growth factor receptor signaling network in head and neck carcinogenesis and implications for targeted therapy. Semin Oncol 2004, 31:734–743.PubMedCrossRefGoogle Scholar
  85. 85.
    Choe MS, Zhang X, Shin HJ, et al.: Interaction between epidermal growth factor receptor- and cyclooxygenase 2-mediated pathways and its implications for the chemoprevention of head and neck cancer. Mol Cancer Ther 2005, 4:1448–1455.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2006

Authors and Affiliations

  • Ann Gillenwater
    • 1
  • Vali Papadimitrakopoulou
  • Rebecca Richards-Kortum
  1. 1.Department of Head and Neck Surgery, Unit 441The University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations