International Journal of Clinical Oncology

, Volume 16, Issue 1, pp 5–14 | Cite as

Oral premalignant lesions: from a clinical perspective

  • Teruo AmagasaEmail author
  • Masashi Yamashiro
  • Narikazu Uzawa
Review Article


In this review article, the clinical and histopathological characteristics of oral premalignant lesions, and primarily oral leukoplakia, are noted and the risk factors for malignant transformation of oral leukoplakia are discussed. Malignant transformation rates of oral leukoplakia range from 0.13 to 17.5%. The risk factors of malignant transformation in the buccal mucosa and labial commissure are male gender with chewing tobacco or smoking in some countries such as India, or older age and/or being a non-smoking female in other countries. Some authors have reported that leukoplakia on the tongue or the floor of the mouth showed a high risk of malignant transformation, although others have found no oral subsites at high risk. In concurrence with some authors, the authors of this review view epithelial dysplasia as an important risk factor in malignant transformation; however, there are conflicting reports in the literature. Many authors believe that nonhomogeneous leukoplakia is a high risk factor without exception, although different terms have been used to describe those conditions. The large size of lesions and widespread leukoplakia are also reported risk factors. According to some studies, surgical treatment decreased the rate of malignant transformation; however, many review articles state that no definitive treatment including surgery can decrease the malignant transformation rate of oral leukoplakia because of the lack of randomized control trials of treatment. Tobacco chewing and smoking may be causative agents for cancerization of oral leukoplakia in some groups, and evidence for a role of human papilloma virus in the malignant transformation of oral leukoplakia is inconsistent. Further research to clarify its role in malignant transformation is warranted.


Oral premalignant lesion Potentially malignant disorders Leukoplakia Erythroplakia Malignant transformation Epithelial dysplasia 


Conflict of interest

No author has any conflict of interest.


  1. 1.
    Kramer IRH, Lucas RB, Pindborg JJ et al (1978) Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 46:518–539CrossRefPubMedGoogle Scholar
  2. 2.
    World Health Organization (1973) Report from a meeting of investigation on histological definition of precancerous lesions. CAN/731, GenevaGoogle Scholar
  3. 3.
    Axell T, Pindborg JJ, Smith CJ et al (1996) Oral white lesions with special reference to precancerous and tobacco-related lesions. J Oral Pathol Med 25:49–54CrossRefPubMedGoogle Scholar
  4. 4.
    Pindborg JJ, Reichart PA, Smith CJ et al (1997) World Health Organization: Histological typing of cancer and precancer of the oral mucosa, 2nd edn. Springer, BerlinGoogle Scholar
  5. 5.
    Warnakulasuriya S, Johnson NW, van der Wall I (2007) Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 36:575–580CrossRefPubMedGoogle Scholar
  6. 6.
    Einhorn J, Wersall J (1967) Incidence of oral carcinoma in patients with leukoplakia of oral mucosa. Cancer (Phila) 20:2189–2193CrossRefGoogle Scholar
  7. 7.
    Roed-Petersen B (1971) Cancer development in oral leukoplakia follow-up of 331 patients. J Dent Res 50:711Google Scholar
  8. 8.
    Silverman S Jr, Bhargava K, Mani NJ et al (1976) Malignant transformation and natural history of oral leukoplakia in 57518 industrial workers of Gujarat, India. Cancer (Phila) 38:1790–1795CrossRefGoogle Scholar
  9. 9.
    Banoczy J, Sugar L (1972) Longitudinal studies in oral leukoplakias. J Oral Pathol 1:265–272CrossRefPubMedGoogle Scholar
  10. 10.
    Gupta PC, Mehta FS, Daftary DR et al (1980) Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10 year follow-up study of Indian villagers. Community Dent Oral Epidemiol 8:287–333CrossRefGoogle Scholar
  11. 11.
    Baric JM, Alman JE, Feldman RS et al (1982) Influence of cigarette, pipe, and cigar smoking, removable partial dentures, and age on oral leukoplakia. Oral Surg Oral Med Oral Pathol 54:424–429CrossRefPubMedGoogle Scholar
  12. 12.
    Pindborg JJ, Jølst O, Renstrup G et al (1968) Studies in oral leukoplakia. A preliminary report on the period prevalence of malignant transformation in leukoplakia based on a follow-up study of 248 patients. J Am Dent Assoc 76:767–771PubMedGoogle Scholar
  13. 13.
    Waldron CA, Shafer WG (1975) Leukoplakia revisited: a clinicopathologic study of 3256 oral leukoplakias. Cancer (Phila) 36:1386–1392CrossRefGoogle Scholar
  14. 14.
    Silverman S Jr, Gorsky M, Lozada F (1984) Oral leukoplakia and malignant transformation: a follow-up study of 257 patients. Cancer (Phila) 53:563–568CrossRefGoogle Scholar
  15. 15.
    Schepman KP, van der Meij EH, Smeele LE et al (1998) Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncol 34:270–275PubMedGoogle Scholar
  16. 16.
    Cowan CG, Gregg TA, Napier SS et al (2001) Potentially malignant oral lesions in northern Ireland: a 20-year population-based perspective of malignant transformation. Oral Dis 7:18–24PubMedGoogle Scholar
  17. 17.
    Saito T, Sugiura C, Hirai A et al (2001) Development of squamous cell carcinoma from pre-existent oral leukoplakia: with respect to treatment modality. Int J Oral Maxillofac Surg 30:49–53CrossRefPubMedGoogle Scholar
  18. 18.
    Amagasa T, Yamashiro M, Ishikawa H (2006) Oral leukoplakia related to malignant transformation. Oral Sci Int 3:45–55Google Scholar
  19. 19.
    Mehta FS, Pindborg JJ, Gupta PC et al (1969) Epidemiologic and histologic study of oral cancer and leukoplakia among 50,915 villagers in India. Cancer (Phila) 24:832–849CrossRefGoogle Scholar
  20. 20.
    Gupta PC (1989) Leukoplakia and incidence of oral cancer. J Oral Pathol Med 18:17CrossRefPubMedGoogle Scholar
  21. 21.
    Roed-Petersen B, Renstrup G (1969) A topographical classification of oral mucosa suitable for electronic data processing its application to 560 leukoplakias. Acta Odont Scand 27:681–695CrossRefPubMedGoogle Scholar
  22. 22.
    Napier SS, Speight PM (2008) Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med 37:1–10CrossRefPubMedGoogle Scholar
  23. 23.
    Nagao T, Ikeda N, Fukano H et al (2005) Incidence rates for oral leukoplakia and lichen planus in a Japanese population. J Oral Pathol Med 34:532–539CrossRefPubMedGoogle Scholar
  24. 24.
    Kirita T, Horiuchi K, Tsuyuki M et al (1995) Clinico-pathological study on oral leukoplakia: evaluation of potential for malignant transformation. Jpn J Oral Maxillofac Surg 41:26–35Google Scholar
  25. 25.
    Pindborg JJ, Renstrup G, Poulsen HE et al (1963) Studies in oral leukoplakias. V. Clinical and histologic signs of malignancy. Acta Odont Scand 21:407–414CrossRefPubMedGoogle Scholar
  26. 26.
    van der Waal I, Schepman KP, van der Meiji EH et al (1997) Oral leukoplakia: a clinicopathological review. Oral Oncol 33:291–301Google Scholar
  27. 27.
    Hansen LS, Olson JA, Silverman S Jr (1985) Proliferative verrucous leukoplakia: a long-term study of thirty patients. Oral Surg Oral Med Oral Pathol 60:285–298CrossRefPubMedGoogle Scholar
  28. 28.
    Shear M, Pindborg JJ (1980) Verrucous hyperplasia of the oral mucosa. Cancer (Phila) 46:1855–1962CrossRefGoogle Scholar
  29. 29.
    Sugár L, Bánóczy J (1969) Follow-up studies in oral leukoplakia. Bull WHO 41:289–293PubMedGoogle Scholar
  30. 30.
    Amagasa T, Michi K, Saito K et al (1977) Clinical classification of oral leukoplakia (in Japanese). Jpn J Oral Maxillofac Surg 23:89–96Google Scholar
  31. 31.
    Dawsey SM, Fleischer DE, Wang GQ et al (1998) Mucosal iodine staining improves endoscopic visualization of squamous dysplasia and squamous cell carcinoma of the esophagus in Linxian, China. Cancer (Phila) 83:220–231CrossRefGoogle Scholar
  32. 32.
    Freitag CP, Barros SG, Kruel CD et al (1999) Esophageal dysplasias are detected by endoscopy with Lugol in patients at risk for squamous cell carcinoma in southern Brazil. Dis Esophagus 12:191–195CrossRefPubMedGoogle Scholar
  33. 33.
    Nakanishi Y, Ochiai A, Yoshimura K (1998) The clinicopathologic significance of small areas unstained by Lugol’s iodine in the mucosa surrounding resected esophageal carcinoma. Cancer (Phila) 82:1454–1459CrossRefGoogle Scholar
  34. 34.
    Shimizu Y, Tsukagoshi H, Fujita M et al (2001) Endoscopic screening for early esophageal cancer by iodine staining in patients with other current or prior primary cancers. Gastrointest Endsc 53:1–5CrossRefGoogle Scholar
  35. 35.
    Maeda K, Suzuki T, Ohyama Y et al (2009) Colorimetric analysis of unstained lesions surrounding oral squamous cell carcinomas and oral potentially malignant disorders using iodine. Int J Oral Maxillofac Surg 39:486–492CrossRefPubMedGoogle Scholar
  36. 36.
    Maeda K, Yamashiro M, Michi Y et al (2009) Effective staining method with iodine for leukoplakia and lesions surrounding squamous cell carcinoma of the tongue assessed by colorimetric analysis. J Med Dent Sci 56:123–130PubMedGoogle Scholar
  37. 37.
    Mehta FS, Shroff BC, Gupta PC et al (1972) Oral leukoplakia in relation to tobacco habits: a ten-year follow-up study of Bombay policeman. Oral Surg Oral Med Oral Pathol 34:426–433CrossRefPubMedGoogle Scholar
  38. 38.
    Kramer IRH (1969) Precancerous conditions of oral mucosa. A computer-aided study. Ann R Coll Surg Engl 45:340–356PubMedGoogle Scholar
  39. 39.
    Silverman S Jr, Rozen RD (1968) Observations on the clinical characteristics and natural history of oral leukoplakia. J Am Dent Assoc 76:772–777PubMedGoogle Scholar
  40. 40.
    Banoczy J (1977) Follow-up studies in oral leukoplakia. J Maxillofac Surg 5:69–75CrossRefPubMedGoogle Scholar
  41. 41.
    Lind PO (1987) Malignant transformation in oral leukoplakia. Scand J Dent Res 95:449–455PubMedGoogle Scholar
  42. 42.
    Gangadharan P, Paymaster JC (1971) Leukoplakia: an epidemiologic study of 1504 cases observed at the Tata Memorial Hospital, Bombay, India. Br J Cancer 25:657–668CrossRefPubMedGoogle Scholar
  43. 43.
    Lan AX, Guan XB, Sun Z (2009) Analysis of risk factors for carcinogenesis of oral leukoplakia. Zhonghua Kou Qiang Yi Xue Za Zhi 44:327–331PubMedGoogle Scholar
  44. 44.
    Chiesa F, Boracchi P, Tradati N et al (1993) Risk of preneoplastic and neoplastic events in operated oral leukoplakias. Oral Oncol Eur J Cancer 29B:23–28CrossRefGoogle Scholar
  45. 45.
    Kramer IRH, El-Labban N, Lee KW (1978) The clinical features and risk of malignant transformation in sublingual keratosis. Br Dent J 144:171–180PubMedGoogle Scholar
  46. 46.
    Pogrel MA (1979) Sublingual keratosis and malignant transformation. J Oral Pathol 8:176–178CrossRefPubMedGoogle Scholar
  47. 47.
    Inoue A, Sakamoto A, Uchida M et al (1985) Malignant progression of oral leukoplakia. J Jpn Soc Cancer Ther 20:18–24Google Scholar
  48. 48.
    Lumerman H, Freedman P, Kerpel S (1995) Oral epithelial dysplasia and the development of invasive squamous carcinoma. Oral Surg Oral Med Oral Pathol 79:321–329Google Scholar
  49. 49.
    Mehta FS, Gupta PC, Pindborg JJ (1981) Chewing and smoking habits in relation to precancer and oral cancer. J Cancer Res Clin Oncol 99:35–39CrossRefPubMedGoogle Scholar
  50. 50.
    Gupta PC, Bhonsle RB, Murti PR et al (1989) An epidemiologic assessment of cancer risk in oral precancerous lesions in India with special reference to nodular leukoplakia. Cancer (Phila) 63:2247–2252CrossRefGoogle Scholar
  51. 51.
    Holmstrup P, Vedtofte P, Reibel J et al (2006) Long-term treatment outcome of oral premalignant lesions. Oral Oncol 42:461–474CrossRefPubMedGoogle Scholar
  52. 52.
    Saito T, Sugiura A, Notani K et al (1999) High malignant transformation rate of widespread multiple oral leukoplakias. Oral Dis 5:15–19CrossRefPubMedGoogle Scholar
  53. 53.
    Mincer HH, Coleman SA, Hopkins KP (1972) Observations on the clinical characteristics of oral lesions showing histologic epithelial dysplasia. Oral Surg Oral Med Oral Pathol 33:389–399CrossRefPubMedGoogle Scholar
  54. 54.
    Bánóczy J, Csiba Á (1976) Occurrence of epithelial dysplasia in oral leukoplakia: analysis and follow-up study of 120 cases. Oral Surg Oral Med Oral Pathol 42:766–774CrossRefPubMedGoogle Scholar
  55. 55.
    Pindborg JJ, Daftary DK, Mehta FS (1977) A follow-up study of sixty-one oral dysplastic precancerous lesions in Indian villagers. Oral Surg Oral Med Oral Pathol 43:383–390CrossRefPubMedGoogle Scholar
  56. 56.
    Pindborg JJ, Reibel J, Holmstrup P (1985) Subjectivity in evaluating oral epithelial dysplasia, carcinoma in situ and initial carcinoma. J Oral Pathol 14:698–708CrossRefPubMedGoogle Scholar
  57. 57.
    Abbey L, Kaugars GE, Gunsolley JC et al (1995) Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol 80:188–191Google Scholar
  58. 58.
    Karabulut A, Reibel J, Therkildsen MH et al (1995) Observer variability in the histologic assessment of oral premalignant lesions. J Oral Pathol Med 24:198–200CrossRefPubMedGoogle Scholar
  59. 59.
    van der Waal I (2009) Potentially malignant disorders of the oral and oropharyngeal mucosa: terminology, classification and present concepts of management. Oral Oncol 45:317–323CrossRefPubMedGoogle Scholar
  60. 60.
    Vedtofte P, Holmstrup P, Hjorting-Hansen E et al (1987) Surgical treatment of premalignant lesions of the oral mucosa. Int J Oral Maxillofac Surg 16:656–664CrossRefPubMedGoogle Scholar
  61. 61.
    Schoelch ML, Sekandari N, Regezi JA et al (1999) Laser management of oral leukoplakias: a follow-up study of 70 patients. Laryngoscope 109:949–953CrossRefPubMedGoogle Scholar
  62. 62.
    Lodi G, Sardella A, Bez C et al (2006) Interventions for treating oral leukoplakia. Cochrane Database Syst Rev; CD001829Google Scholar
  63. 63.
    Lodi G, Porter S (2008) Management of potentially malignant disorders: evidence and critique. J Oral Pathol Med 37(2):63–69CrossRefPubMedGoogle Scholar
  64. 64.
    Zhang L, Poh CF, Lam WL et al (2001) Impact of localized treatment in reducing risk of progression of low-grade oral dysplasia: molecular evidence of incomplete resection. Oral Oncol 37:505–512CrossRefPubMedGoogle Scholar
  65. 65.
    Roodenburg JL, Panders AK, Vermey A (1991) Carbon dioxide laser surgery of oral leukoplakia. Oral Surg Oral Med Oral Pathol 71:670–674CrossRefPubMedGoogle Scholar
  66. 66.
    Ishii J, Fujita K, Munemoto S et al (2004) Management of oral leukoplakia by laser surgery: relation between recurrence and malignant transformation and clinicopathological features. J Clin Laser Med Surg 22:27–33CrossRefPubMedGoogle Scholar
  67. 67.
    Browne RM, Potts AJC (1986) Dysplasia in salivary gland ducts in sublingual leukoplakia and erythroplakia. Oral Oncol 62:44–49Google Scholar
  68. 68.
    Hays GL, Lippman SM, Flaitz CM et al (1995) Co-carcinogenesis and field cancerization: oral lesions offer first signs. J Am Dent Assoc 126:47–51PubMedGoogle Scholar
  69. 69.
    Scholes AG, Woolgar JA, Boyle MA et al (1998) Synchronous oral carcinomas: independent or common clonal origin? Cancer Res 58:2003–2006PubMedGoogle Scholar
  70. 70.
    Lele S (2005) Although leukoplakia responds to some treatments relapses and adverse effects are common. Evid Based Dent 6:15–16CrossRefPubMedGoogle Scholar
  71. 71.
    Lodi G, Sardella A, Bez C et al (2002) Systematic review of randomized trials for the treatment of oral leukoplakia. J Dent Educ 66:896–902PubMedGoogle Scholar
  72. 72.
    Epstein JB, Gorsky M (1999) Topical application of vitamin A to oral leukoplakia: a clinical case series. Cancer (Phila) 86:921–927CrossRefGoogle Scholar
  73. 73.
    Epstein JB, Gorsky M, Wong FLW et al (1998) Topical bleomycin for the treatment of dysplastic oral leukoplakia. Cancer (Phila) 83:629–634CrossRefGoogle Scholar
  74. 74.
    Shiu MN, Chen THH, Chang SH et al (2000) Risk factors for leukoplakia and malignant transformation to oral carcinoma: a leukoplakia cohort in Taiwan. Br J Cancer 82:1871–1874CrossRefPubMedGoogle Scholar
  75. 75.
    Yen AM, Chen SC, Chang SH et al (2008) The effect of betel quid and cigarette on multistate progression of oral pre-malignancy. J Oral Pathol Med 37(7):417–422CrossRefPubMedGoogle Scholar
  76. 76.
    Miller CS, White DK (1996) Human papillomavirus expression in oral mucosa, premalignant conditions and squamous cell carcinoma: a retrospective review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 82:57–68CrossRefPubMedGoogle Scholar
  77. 77.
    Campisi G, Giovannelli L, Ammatuna P et al (2004) Proliferative verrucous vs. conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol 40:835–840CrossRefPubMedGoogle Scholar
  78. 78.
    Palefsky JM, Silverman S Jr, Abdel-Salaam M et al (1995) Association between proliferative verrucous leukoplakia and infection with human papillomavirus type 16. J Oral Pathol Med 24:193–197CrossRefPubMedGoogle Scholar
  79. 79.
    Bouda M, Gorgoulis VG, Kastrinakis NG et al (2000) High risk HPV types are frequently detected in potentially malignant and malignant oral lesions, but not in normal mucosa. Mod Pathol 13:644–653CrossRefPubMedGoogle Scholar
  80. 80.
    Gillison L, Koch WM, Capone RB et al (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92:721–728CrossRefGoogle Scholar
  81. 81.
    Miller CS, Johnstone BM (2001) Human papillomavirus as a risk factor for oral squamous cell carcinoma: a meta-analysis, 1982–1997. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 91:622–635CrossRefPubMedGoogle Scholar
  82. 82.
    Chang KC, Su IJ, Tsai ST et al (2002) Pathological features of betel quid-related oral epithelial lesions in Taiwan with special emphasis on the tumor progression and human papillomavirus association. Oncology 63:362–369CrossRefPubMedGoogle Scholar
  83. 83.
    Szarka K, Tar I, Fehér E et al (2009) Progressive increase of human papillomavirus carriage rates in potentially malignant and malignant oral disorders with increasing malignant potential. Oral Microbiol Immunol 24(4):314–318CrossRefPubMedGoogle Scholar
  84. 84.
    Campisi G, Panzarella V, Giuliani M et al (2007) human papillomavirus: its identikit and controversial role in oral oncogenesis, premalignant and malignant lesions. Int J Oncol 30:813–823 (Review)PubMedGoogle Scholar
  85. 85.
    Fouret P, Martin F, Flahault A et al (1995) Human papillomavirus infection in malignant and premalignant head and neck epithelium. Diagn Mol Pathol 4:122–127CrossRefPubMedGoogle Scholar
  86. 86.
    Gassenmaier A (1988) Papilloma virus DNA (HPV) in leukoplakia and cancerous alterations of the oral mucosa. Dtsch Z Mund Kiefer Gesichtschir 12:149–151PubMedGoogle Scholar
  87. 87.
    Gassenmaier A, Hornstein OP (1988) Presence of human papilloma-virus DNA in benign and precancerous oral leukoplakia and squamous cell carcinomas. Dermatologica 176:224–233CrossRefPubMedGoogle Scholar
  88. 88.
    Perrons C, Brink N, Jalal H et al (2005) The impact of high risk human papillomavirus testing an inner London colposcopy clinic. J Med Virol 76:576–582CrossRefPubMedGoogle Scholar
  89. 89.
    Lee SY, Cho NH, Choi EC et al (2010) Relevance of human papilloma virus (HPV) infection to carcinogenesis of oral tongue cancer. Int J Oral Maxillofac Surg 39:678–683CrossRefPubMedGoogle Scholar
  90. 90.
    Yang SW, Lee YS et al (2009) Human papillomavirus in oral leukoplakia is no prognostic indicator of malignant transformation. Cancer Epidemiol 33(2):118–122CrossRefPubMedGoogle Scholar
  91. 91.
    Acay R, Rezende N et al (2008) Human papillomavirus as a risk factor in oral carcinogenesis: a study using in situ hybridization with signal amplification. Oral Microbiol Immunol 23(4):271–274CrossRefPubMedGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2011

Authors and Affiliations

  • Teruo Amagasa
    • 1
    Email author
  • Masashi Yamashiro
    • 1
  • Narikazu Uzawa
    • 1
  1. 1.Maxillofacial Surgery, Graduate SchoolTokyo Medical and Dental UniversityTokyoJapan

Personalised recommendations