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A quarter-century before Schwimmer of Budapest  coined the term "leukoplakia", and a full half-century before the very concept of premalignancy was accepted, Sir James Paget had recognized the lesion's cancer-transforming potential and its relationship to pipe smoking, reporting on "leukokeratosis" and "smoker's patch" as early as 1851.[2,3] One hundred and forty years later oral leukoplakia is well established as one of the very best examples of premalignancy in man.[4-7] The management of such lesions is now a routine facet of the practice of dentistry.
The precancerous nature of leukoplakia was initially suspected because a large number were found in close proximity to mucosal carcinomas, especially in arsenic-treated syphilis patients.[1,3,8-10] Later investigation found dysplastic and/or microinvasive epithelium in 17-25% of leukoplakia biopsy samples.[11-13] But true premalignancy was not proven until large numbers of leukoplakias were followed for long periods of time. For half a century now rates of malignant transformation have been available from numerous follow-up studies (Table 1, below).
Such studies have not only proven premalignancy, but have helped us to recognize that certain clinical features of leukoplakia can be strong predictors of future risk, stronger predictors than much more sophisticated contemporary laboratory tests. Inconsistencies in the design and reporting of clinical investigations have, unfortunately, resulted in such a wide variance in transformation rates that it is difficult to know which to accept. Basic disease characteristics such as lesion size, duration, multiplicity, etiologic factors, etc. have been largely ignored, and only recently has a precancer staging system been proposed which can assure uniformity between future follow-up investigations. Until such a system is in effect, however, it is inappropriate to do more than suggest a range of malignant transformation rates. Table 1 indicates that this range varies from 3-20%, but specific leukoplakia subtypes, to be mentioned later, have been associated with rates as high as 40%.
It should be emphasized that leukoplakia is not only the most common oral precancer, representing 85% of such lesions, but it is also the most common of all chronic lesions of the oral mucosa, affecting 3% of white adults (Table 2).[25,26] As only one leukoplakia in four is ever biopsied, as biopsy sites are determined by clinical evaluation, and as follow-up consists predominantly of clinical examination, it is incumbent upon every dental practitioner to be familiar with its clinical features.
The first recorded white oral plaque was an "ichthyosis" reported in 1818 by Alibert of Paris. From that inception the early literature on white lesions has tended to hinder rather than aid our understanding. More than any other oral disease, leukoplakia has suffered from an excess of diagnostic terms and definitions; at least 75 have been used thus far. This has led to such confusion that many clinicians refuse to use any term beyond a simple "white patch", and the term is no longer used to describe similar lesions of the urogenital tract. Nevertheless, the name is a good one, as was recognized by the World Health Organization when it provided the clinical definition which is now generally accepted for oral leukoplakia: a keratotic white plaque that cannot be scraped off and cannot be given another specific diagnostic name. It is no longer acceptable to presume that microscopic evidence of dysplasia is necessary for this diagnosis, and in retrospect it seems surprising that microscopy was ever considered essential to the diagnosis of a lesion which is typically not biopsied.
Leukoplakia, then, is a clinical diagnosis which has the unusual attribute of being dependent not so much on definable appearances as on the exclusion of other lesions which present as oral white plaques. Such lesions as lichen planus, chronic cheek bite, frictional keratosis, tobacco pouch keratosis, nicotine palatinus, leukoedema, white sponge nevus, etc. must be ruled out before a diagnosis of leukoplakia can be made. This concept confuses many, but is not unparalleled in dentistry. Juvenile periodontitis (periodontosis) also requires that all systemic diseases capable of producing periodontal destruction (e.g. neutropenia, juvenile diabetes, histiocytosis X) be ruled out before the term can be used as a diagnosis.
The etiology of leukoplakia remains unknown. Many physical agents have been proposed, including tobacco, alcohol, chronic friction, electrogalvanic reaction between unlike restorative metals, and ultraviolet radiation.[6,18] Tobacco smoking is by far the most accepted factor, although obvious smoke-related keratotic changes such as nicotine palatinus (smoker's palate) are legitimately excluded from the diagnosis of leukoplakia. The cancer risk in nicotine palatinus is so low, surprizingly, that it appears to be nonexistent and most authorities no longer consider it to be a precancerous lesion except in persons who practice reverse-smoking (smoking with the lit end of a cigar or cigarette in the mouth).[4-6] Clinical changes in this lesion appear to be largely related to thermal iritation and disappear within a few weeks of habit cessation.[39,40]
The evidence for a tobacco smoking etiology for leukoplakia, however, is quite strong. Not only do 70-90% of leukoplakia patients have such a habit, but 78% of lesions either completely disappear (58%) or regress within 12 months after smoking cessation.[4-6,41] Ironically, leukoplakias remaining after habit cessation or in persons who have never smoked may have a higher risk of malignant transformation than leukoplakias in smokers.[6,17]
Tobacco chewing is similar to nicotine palatinus in that it produces a nonleukoplakic keratosis which is, unlike true leukoplakia, routinely and completely reversible after habit cessation. In these cases the term leukoplakia should be used only for those white plaques remaining two or more months after the patient quits his or her tobacco habit. Smokeless tobacco keratosis, furthermore, has a different histology and a much smaller risk of cancer than has leukoplakia.[42,43]
Ultraviolet radiation is also an accepted etiologic factor for leukoplakias, but only those associated with actinic cheilitis or "farmer's lip." Bouquot et al  have demonstrated that two-thirds of all lip vermilion carcinomas are associated with leukoplakia. This is the strongest association for any cancer of the upper aerodigestive tract.
Chronic mechanical irritation is no longer considered important to the production of precancerous leukoplakia. Such obvious traumatic lesions as linea alba and chronic cheek bite have never been reported to have transformed into malignancies. White lesions produced by mechanical irritation are best considered as frictional keratoses, which have no potential for malignant transformation.
Microorganisms have been implicated in leukoplakia etiology for more than a century, beginning with the classic dorsal leukoplakia of syphilitic glossitis.[1,3,6] Today tertiary syphilis is rare, but a fungus, Candida albicans, is ubiquitous and is so often found in Phase III and IV lesions that the terms "candida epithelial hyperplasia" and "candida leukoplakia" are commonly used to describe them.[6,22,44] It is not known whether this yeast produces dysplasia or secondarily infects previously altered epithelium, but some leukoplakias have disappeared or become altered to a lower Phase level after topical antifungal therapy.
Recently developed molecular biology and virology techniques have allowed investigators, for the first time, to identify human papillomavirus in leukoplakia and oral cancer.[45,46] Detection rates are similar to normal oral epithelium, however, and such techniques have not yet been applied to large numbers of followed patients. It is, nevertheless, very significant that HPV type 16, a type demonstrated in oral leukoplakias and carcinomas, has been shown to induce dysplasia in squamous epithelium in an otherwise sterile in vitro environment.
Oral leukoplakia has always been a predominantly male disease, except in regional populations in which women use tobacco products more than men.[3-13,19,29] In the United States a slight decrease has been noted in this male predilection: 74% of affected persons were males in 1935, compared to 69% in 1988. This decrease is a welcome change, as leukoplakias in males have a much higher risk of dysplasia or malignant transformation than similar lesions in females. Overall, the disease is more frequently diagnosed now than in 1935, but this is probably because of enhanced awareness rather than because of a real increase in incidence.
This precancer usually affects persons over 40 years of age.[1-13,19,29] Prevalence increases rapidly with age, especially for males. While fewer than 1% of males prior to 30 years of age have lesions, an alarming 8% of males beyond 70 years of age are affected. This may have grave implications for the practice of dentistry as the U.S. population ages. The average age of affected persons, 60 years, is similar to the average age for oral cancer patients, although some studies have found it to occur about five years earlier than cancer.[6,13]
Oral leukoplakias account for 80% of all leukoplakias of the upper aerodigestive tract.[19,37] Most of the others are vocal cord lesions and are referred to as laryngeal keratoses, but have an appearance and biological behavior indistinguishable from leukoplakia.[36,37]
More than two-thirds of all oral leukoplakias are found at three sites: lip vermilion, buccal mucosa and gingiva. Sites at which leukoplakias are most likely to be associated with malignancy are, however, somewhat different: the tongue, lip vermilion and oral floor.[13,19] The latter three sites, in fact, account for 93% of all oral leukoplakias with dysplasia or carcinoma. Gingival leukoplakias, on the other hand, seldom become malignant or dysplastic, perhaps because most of them are really examples of misdiagnosed "frictional keratoses" or calluses.
Leukoplakia has a varied clinical appearance and its appearance frequently changes over time. Change or progression over time accounts for yet another unique aspect of leukoplakia: it is one of the few diseases in which long duration is not evidence of harmless future behavior. Lesions of long duration have a greater risk of malignant transformation than those of short duration, and the older a leukoplakia the worse is its prognosis.[4-7,22] The average duration at diagnosis is 2.4 years. Carcinomas arising from leukoplakias usually occur 2-4 years after the onset of the white plaque, but may occur decades later.[19,22] Transformation does not appear to be dependent on the age of the affected patient.
Leukoplakias begin as thin gray or gray/white plaques which may appear somewhat translucent, are sometimes fissured or wrinkled, and are typically soft and flat. They usually have sharply demarcated borders but occasionally blend gradually into normal mucosa. This early stage is sometimes referred to as preleukoplakia, [4,25,29] but is preferably designated thin leukoplakia. In fact, the extreme confusion surrounding the various descriptive diagnostic terms used for leukoplakia subtypes has led the present authors to propose that we eliminate them entirely and use the oral cancer Staging concept as a model for leukoplakia classification by "Phases" (Table 2). Thin leukoplakia under such a system would be a Phase I leukoplakia.
Thin leukoplakia may disappear or continue unchanged, but as time progresses as many as 2/3 of such plaques extend slowly laterally and acquire a distinctly white appearance from a thickening keratin layer (Figures 1 and 2). They may become leathery to palpation and fissures may deepen, but there should be only a few, if any, localized nodules or surface projections if they are to be given the next most "severe" diagnosis: Phase II leukoplakia (homogeneous or thick, smooth, perhaps fissured leukoplakia). Most Phase II lesions remain indefinitely in this Phase but some, perhaps as many as one-third, regress or disappear and a few become even more severe.[4-6,17]
The latter lesions begin to develop surface irregularities of a nodular or granular nature, hence are referred to as granular or nodular leukoplakia (Figure 3). Occasionally, pointed projections develop on the surface and may be so numerous that the resulting lesions are called verruciform leukoplakia. Both types are Phase III lesions with similar prognoses. It should be mentioned, furthermore, that hairy leukoplakia, seen on the lateral tongues and buccal commissures of HIV infected patients, is a distinctive, rapid-onset, nonpremalignant keratosis with similarities to verruciform leukoplakia, but is not a true leukoplakia. It is, rather, a keratin hyperplasia presumably induced by the Epstein-Barr virus and is perhaps better termed "oral HIV keratosis".
Phase III leukoplakias may become dysplastic, even invasive, with no change whatsoever in the clinical appearance. An additional surface change can occur over time, however. Multiple circular or oval patches of nonblanching redness or "erythroplakia" begin appearing in scattered areas (Figure 4). Such areas presumably represent sites in which epithelial cells are so immature that they are no longer able to produce keratin. These intermixed red-and-white Phase IV lesions (erythroleukoplakia, speckled leukoplakia, nonhomogeneous leukoplakia), are the most worrisome form of the disease and carry an extremely high risk of malignant transformation.[4,8,17] Their multiplicity, moreover, is strong support for the multicentric-origin theory of cancer, a theory which originated from studies of oral carcinomas. It has been demonstrated, incidentally, that oral cancers associated with leukoplakia have a better prognosis than those which arise without juxtapositioned leukoplakia, regardless of the Phase level at the time of diagnosis.
Erythroplakia is typically diagnosed microscopically as severe epithelial dysplasia or carcinoma in situ.[10,33] It may occur without leukoplakia, and has been noted in a majority of early oral cancers. Some cancer experts have so emphasized erythroplakia that they criticize investigators still interested in the more common but less worrisome white lesions. While leukoplakias are diagnosed 77 times more often than erythroplakias, beneficial results have accrued from the emphasis on red: the proportion of oral carcinomas diagnosed in the very earliest, preinvasive, red stage, i.e. the carcinoma in situ stage, is greater now than it was half a century ago.
Figure 5 provides a composite illustration of the various clinical appearances of leukoplakia with expected underlying microscopic changes. Lesions become progressively more "severe" or have an increasing risk of cancer development as they approach the right edge, that is, change from Phase I to Phase IV lesions. This figure does not necessarily represent a chronological change, but rather the potential presentations of leukoplakia. Lesions may be multiple or present with multiple appearances, in which case the clinician should use the highest Phase category for the clinical diagnosis of the entire lesion and should also use it to determine the best area for biopsy. No Phase III or IV leukoplakia should go without biopsy sampling, although Phase I and II lesions are frequently and justifiably followed by clinical examination only.
Pathology and Differential Diagnosis
Leukoplakia demonstrates a thickened surface layer of parakeratin, sometimes orthokeratin. Basilar cells and keratinocytes in the lower portions of the epithelium usually show no evidence of dysplasia, besides a mild basilar hyperplasia, but about 10% of cases will be dysplastic and these have an elevated risk of malignant transformation. The reader is referred to the discussion of epithelial dysplasia elsewhere in this text.
Treatment and Prognosis
Conservative surgical excision remains the treatment of choice for small leukoplakias. Electrocautery, cryosurgery and laser ablation appear to be equally effective, although thermal excision tends to hinder a pathologist's ability to evaluate extension and degree of dysplasia. The key is long-term follow-up after removal, because recurrences are frequent and additional leukoplakias occur. Clinical evaluation every six months is recommended, every 2-3 months for Phase IV lesions. Treatment sites remaining disease free for three years need no longer be followed, but any patient with residual leukoplakia should be followed for a lifetime.
Multiple biopsies of Phase III and IV areas of large, multiple, or recurrent lesions are essential and should be followed by removal of all dysplastic tissue identified. Even moderate epithelial dysplasias should be removed, as recent research from laryngeal keratosis has identified a significant risk of malignant transformation.[48,49]
Early carcinomas, of course, should be looked for as well as new or altered precancers. Oral cancers are typically painless but can be detected by a color change to erythroplakia or erythroleukoplakia, an increased firmness (induration), unexplained hemorrhage, chronic ulcer formation, or mass formation (white or red, usually with surface pebbling or ulceration).[10,34] With early detection the prognosis is excellent and surgical deformity can be minimal. Small, early oral cancers are so readily and easily removed, in fact, that Bouquot et al. have classified lip vermilion cancers as among the few cancers currently capable of complete cure. They found no vermilion-related cancer morbidity or mortality during a 54-year observation period of a large number of affected patients representing all vermilion cancers in an American community. With proper attention to the above protocol there is no reason to presume a lesser prognosis for intraoral mucosal sites, at least for those cancers associated with precancerous lesions such as leukoplakia.
References (Chronologic Order)
Note: For general references click on link to the left.
1. Schwimmer, E. Die idiopathischen Schleimhautplauques der Mundhohle (Leukoplakia buccalis). Arch Dermat Syph 9:611-570, 1877.
2. Quoted in Paget, J.. Cancer following ichthyosis of the tongue. Tans Clin Soc Lond 3:88, 1870.
3. Quoted in: Prinz, H. Leukoplakia oris -- a clinical study. Dent Cosmos 70:663-672, 1928.
4. Pindborg, J.J. Oral cancer and precancer. Bristol: John Wright and Sons, Ltd, 1980.
5. Banoczy, J. Oral leukoplakia. The Hague: Martinus Nijhoff Publishers, 1982.
6. Bouquot JE. Epidemiology. In: Gnepp DG: Pathology of the head and neck. New York: Churchill Livingstone, 1987, pp 263-314.
7. Bouquot, J.E. Reviewing oral leukoplakia-clinical concepts for the 1990s. J Amer Dent Assoc 122:80-82, 1991.
8. King, H., Hamilton, C.M. Leukoplakia buccalis -- a study of 80 cases. South Med J 24:380-391, 1931.
9. Hobaek, A. Leukoplakia oris. Acta Odont Scand 7:61-91, 1946.
10. Bouquot, JE, Weiland, L.H., Kurland, L.T. Leukoplakia and carcinoma in situ synchronously associated with invasive oral/pharyngeal carcinoma in Rochester, Minnesota, 1935-1984. Oral Surg 65:199-207, 1988.
11. Pindborg, J.J., Renstrup, G., Poulsen, H.E., Silverman, S. Jr. Studies in oral leukoplakias. V. Clinical and histological signs of malignancy. Acta Odont Scand 21:407-414, 1963.
12. Waldron, C.A., Shafer, W.G. Leukoplakia revisted: a clinicopathologic study of 3256 oral leukoplakias. Cancer 36:1386-1392, 1975.
13. Bouquot, J.E., Gorlin, R.J. Leukoplakia, lichen planus and other oral keratoses in 23,616 white Americans over the age of 35 years. Oral Surg 61:373-381, 1986.
14. Roed-Petersen, B. Cancer development in oral leukoplakia: follow-up of 331 patients. J Dent Res 50:711, 1971.
15. Einhorn, J., Wersall, J. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer 20:2189-2193, 1967.
16. Pindborg, J.J., Jolst, O., Renstrup, G., Roed-Petersen, B. Studies in oral leukoplakia. J Amer Dent Assoc 76:767-771, 1968.
17. Kramer, I.R.H., Lucas, R.B., El-Labban, N., et al. A computer-aided study on the tissue changes in oral keratoses and lichen planus, and an analysis of case groupings by subjective and objective criteria. Br J Cancer 29:408-426, 1970.
18. Banoczy, J. Follow-up studies in oral leukoplakia. J Max Fac Surg 5:69- 75, 1977.
19. Bouquot, J., Weiland, L., Ballard, D., Kurland, L. Leukoplakia of the mouth and pharynx in Rochester, MN, 1935-1984; incidence, clinical features and follow-up of 463 patients from a relatively unbiased patient pool. J Oral Path 17:436, 1988.
20. Maerker, R., Burkhardt, A. Klinik oraler Leukoplakien und Prakanzerosen. Retrospektive Studie an 200 Patienten. Dtsch Z Mund Kiefer GesichtsChir 2:206-211, 1978.
21. Sturgis, S.H., Lund, C.C. Leukoplakia buccalis and keratosis labialis. NEJM 210:996-1006, 1934.
22. Silverman, S., Gorsky, M., Lozada, F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 53:563-568, 1984.
23. Leonardelli, G.B., Talamazzi, F. Leucoplasie del caro orale e precancerosi. Nota I. Arch Ital Otol 61:107-114, 1950.
24. Bouquot, J.E., Gundlach, K.K.H. A new staging protocol for oral leukoplakia. Presented at the annual meeting of the German Association of Plastic Surgeons in Frankfort, Germany; July, 1992.
25. Axell, T. A prevalence study of oral mucosal lesions in an adult Swedish population. Odont Revy 27 (suppl 26):1-103, 1976.
26. Bouquot, J.E. Common oral lesions found during a mass screening examination. J Amer Dent Assoc 112:50-57, 1986.
27. Jenson, A.B., Lancaster, W.D., Kurman, R.J. Uterine cervix. In: Henson, D.E., Albores-Saavedra, J. The pathology of incipient neoplasia. Philadelphia: W.B. Saunders Co., 1986, pp. 249-263.
28. WHO Collaborating Centre for Oral Precancerous Lesions. Definitions of leukoplakia and related lesions: an aid to studies on oral precancers. Oral Surg 46:518-539, 1978.
29. Axell, T. Occurrence of leukoplakia and some other oral white lesions among 20333 adult Swedish people. Community Dent Oral Epidemiol 15:46-51, 1987.
30. Greenspan, J.S., Greenspan, D. Oral hairy leukoplakia: diagnosis and management. Oral Surg 67:396-403, 1989.
31. Hansen, L.S., Olson, J.A., Silverman, S.: Proliferative verrucous leukoplakia. Oral Surg 60:285-298, 1985.
32. Slaughter, D.P., Southwick, H., Smejkol, W.: "Field cancerization" in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 6:963-968, 1953.
33. Shafer, W.G., Waldron, C.A. Erythroplakia of the oral cavity. Cancer 36:1021-1024, 1975.
34. Mashberg, A., Samit, A.M. Early detection, diagnosis, and management of oral and oropharyngeal cancer. CA 39:67-88, 1989.
35. Bouquot, J.E., Kurland, L.T., Weiland, L.H. Carcinoma in situ of the upper aerodigestive tract: incidence, time trends and follow-up in Rochester, Minnesota, 1935-1984. Cancer 61:1691-1698, 1988.
36. Bouquot, J.E., Gnepp, D.R. Laryngeal precancer--a review of the literature, commentary and comparison with oral leukoplakia. Head Neck 1991; 13: 488-497.
37. Bouquot, J.E., Kurland, L.T., Weiland, L.H. Laryngeal keratosis and carcinoma in the Rochester, MN, population, 1935-1984. Cancer Detect Prevent 15:83-91, 1991.
38. Bouquot, J.E., Crout, R.J.: Odd gums: the prevalence of common gingival and alveolar lesions in 23,616 white Americans over 35 years of age. Quint Internat 19:747-753, 1988.
39. Rossie K.M., Guggenheimer, J.: Thermally induced 'nicotine' stomatitis: a case report. Oral Surg 70:597-599, 1990.
40. Regezi, J.A., Sciubba, J.J. Oral pathology; clinical-pathologic correlations. Philadelphia: W.B. Saunders, 1989, pp. 92-93.
41. Roed-Petersen, B. Effect on oral leukoplakia of reducing or ceasing tobacco smoking. Acta Dermato-Venereol 62:164-167, 1982.
42. Axell, T. The relation of the clinical picture to the histopathology of snuff dipper's lesions in a Swedish population. J Oral Path 5:229-236, 1976.
43. Bouquot, J.E., Glover, E.D., Schroeder, K.L. Leukoplakia and smokeless tobacco keratosis are two separate precancers. In: Varma, A.D. (ed). Oral oncology. Dehli: MacMillan India, Ltd, 1991, pp. 67-69 (vol 2).
44. Krogh, P., Homstrup, P., Thorn, J.J., et al. Yeast species and biotypes associated with oral leukoplakia and lichen planus. Oral Surg 63:48-54, 1987.
45. Greer, R.O., Eversole, L.R. Leukoplakia, verruciform hyperkeratosis, verrucous carcinoma, and squamous carcinoma associated with human papillomavirus. Oral Surg 68:598, 1989.
46. Kashima, H.K., Kutcher, M., Kessis, T., et al. Human papillomavirus in squamous cell carcinoma, leukoplakia, lichen planus, and clinically normal epithelium of the oral cavity. Ann Otol Rhinol Laryngol 99:55-61, 1990.
47. McCance, D.J., Kopan, R., Fuchs, E., et al. Human papillomavirus type 16 alters human epithelial cell differentiation in vitro. Proc Natl Acad Sci USA 85:7169-7173, 1988.
48. Velasco, J.R.R., Nieto, C.S., de Bustos, C.P., et al. Premalignant lesions of the larynx; pathological prognostic factors. J Otolaryngol 16:367-370, 1987.
49. Hojslet, P.E., Moesgaard Nielsen, V., Palvio, D. Premalignant lesions of the larynx. Acta Otolaryngol (Stockh) 107:150-155, 1989.
50. Bouquot, J.E., Ballard, D.J., Kurland, L.T., Beard, C.M., et al. Comparison of carcinomas of the skin, mucosa and vermilion border of the lips in residents of Rochester, Minnesota, 1935-1984. Toronto, Canada: Bulletin of the Annual Meeting of the American Academy of Oral Pathology, 1986.
Table 1: Malignant transformation rates (%) of the largest leukoplakia follow-up studies from Europe and the United States, ranked by sample size (modified from Bouquot JE, Whitaker SB. Quint Internat 1994; 25:133-140).
* includes 13 cases from the pharynx.
Table 2: Gender-specific prevalence rates per 1,000 population for selected oral masses and surface alterations in U.S. adults, ranked by total frequency. Modified from Bouquot JE. Common oral lesions found during a mass screening examination. J Am Dent Assoc 1986; 112:50-57, and Bouquot JE, Gundlach KKH. Oral exophytic lesions in 23,616 white Americans over 35 years of age. Oral Surg Oral Med Oral Pathol 1986; 62:284-291.
* total examined population = 23,616 adults over 35 years of age
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