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Leukoplakia, Oral
Article Last Updated: Jul 11, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Crispian Scully, MD, PhD, CBE, MDS, Professor, Dean, Director of Studies and Research, and Eastman Dental Institute for Oral Health Care Sciences, International Centers for Excellence in Dentistry, University of London, UK
Editors: David P Fivenson, MD, Director, Wound Care Service, Department of Dermatology, Henry Ford Health System; Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center; Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey; Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
leukoplakia, keratosis, oral leukoplakia
Background
The World Health Organization first defined oral leukoplakia as a white patch or plaque that could not be characterized clinically or pathologically as any other disease; therefore, lichen planus, candidiasis, and white sponge nevus were excluded. At the 1983 international seminar, the current definition was composed:
Leukoplakia is a whitish patch or plaque that cannot be characterized clinically or pathologically as any other disease, and is not associated with any physical or chemical causative agent, except the use of tobacco.
Oral white lesions include leukoplakias (as defined above), keratoses, leukoplakias of clear infective origin (candidal, syphilitic, hairy leukoplakia associated with Epstein-Barr virus), candidosis, lichen planus, oral submucous fibrosis, lupus erythematosus, dyskeratosis congenita, and frank carcinomas.
Pathophysiology
No etiologic factor can be identified for most persistent oral white plaques (ie, idiopathic leukoplakia). The histopathologic features are highly variable, ranging from hyperkeratosis and hyperplasia to atrophy and severe dysplasia.
Patients with idiopathic leukoplakia have the highest risk of developing cancer. In studies of these patients, 4-17% had malignant transformation of the lesions in less than 20 years. The risk of developing malignancies at lesion sites is 5 times greater in patients with leukoplakia than in patients without leukoplakia.
Dysplastic lesions do not have any specific clinical appearance; however, where erythroplakia is present, dysplasia is likely.
Dysplasia is evident in 17-25% of biopsy samples of leukoplakias. Erythroleukoplakias, verrucous leukoplakias, and nodular leukoplakias show an increasing frequency of dysplastic histologic changes or aneuploidy.
Leukoplakias that are speckled, or erythroleukoplakic, are usually dysplastic or frank carcinomas. Nodular or verrucous lesions are also sinister, but homogenous leukoplakias are far less likely to be potentially malignant.
Most idiopathic leukoplakias are homogenous leukoplakias and show little evidence of dysplastic histologic changes or aneuploidy. However, studies have revealed carcinoma or severe dysplasia in the excision specimens of approximately 5% of leukoplakias excised when the diagnostic biopsy specimens had revealed no dysplasia.
Carcinoma in situ is a controversial term used for severe dysplasia in which the abnormalities extend throughout the thickness of the epithelium. All the cellular abnormalities characteristic of malignancy may be present; only invasion of the underlying connective tissue is absent. Top-to-bottom epithelial dysplasia, like other dysplastic lesions, has no characteristic clinical appearance, although erythroplasia often proves to be carcinoma in situ or early invasive carcinoma.
Frequency
United States
Oral leukoplakia is uncommon, possibly occurring in less than 1% of adults.
International
The rates are the same as those in the United States.
Mortality/Morbidity
Some leukoplakias culminate in oral squamous cell carcinoma (OSCC).
Race
An increased prevalence is observed in communities and races with high tobacco use, such as Southeast Asia.
Sex
Males have the highest incidence of leukoplakias.
Age
Leukoplakias are usually seen in adults older than 40 years.
History
Leukoplakias are usually asymptomatic and are initially noticed by a dentist during a routine examination.
Physical
Leukoplakias are white lesions that cannot be removed with a gauze swab.
- Most leukoplakias are smooth, white plaques (homogeneous leukoplakias).
- Most leukoplakias occur on the lip, the buccal mucosae, or the gingivae.
- Some leukoplakias are white and warty (verrucous leukoplakia).
- Some leukoplakias are mixed white and red lesions (erythroleukoplakias or speckled leukoplakias).
- Dysplastic lesions do not have any specific clinical appearance; however, where erythroplasia is present, dysplasia, carcinoma in situ, and frank carcinomas are more likely to be seen.
- The site of the lesion is relevant; leukoplakias on the floor of the mouth or on the ventrum of the tongue and the lip are sinister.
- The size of the lesion appears to be irrelevant. Even small dysplastic lesions may lead to multiple carcinomas and a fatal outcome.
Causes
No etiologic factor can be identified for most persistent oral leukoplakias (idiopathic leukoplakia).
- Known causes of leukoplakia include the following:
- Trauma (eg, chronic trauma from a sharp or broken tooth or from mastication may cause keratosis)
- Tobacco use: Chewing tobacco is probably worse than smoking.
- Alcohol
- Infections (eg, candidosis, syphilis, Epstein-Barr virus infection): Epstein-Barr virus infection causes a separate and distinct non–premalignant lesion termed hairy leukoplakia.
- Chemicals (eg, sanguinaria)
- Immune defects: Leukoplakias appear to be more common in transplant patients.
Burns, Chemical
Lichen Planus
Other Problems to be Considered
Drug abuse
Procedures
- Perform an oral biopsy.
- The recently introduced, computer-assisted, oral brush biopsy is a detection tool providing evidence of cellular abnormalities in precancerous and cancerous lesions. With the aid of a highly specialized, neural, network-based, image-processing system specifically designed to detect oral epithelial precancerous and cancerous cells, the pathologist can detect as few as 1 or 2 abnormal individual cells in several hundred thousand cells.
- The detection of 1 or 2 such abnormal cells is sufficient to warrant a histologic specimen obtained by scalpel biopsy.
Histologic Findings
The histopathologic features are highly variable, ranging from hyperkeratosis and hyperplasia to atrophy and severe dysplasia. The histologic assessment of oral epithelial dysplasia is notoriously unreliable. Many studies show interpathologist and intrapathologist variation in diagnosing dysplasia. Clearly, molecular studies are indicated to introduce more objectivity. Studies of p53 and other molecular markers, loss of heterozygosity, and DNA ploidy as molecular markers are currently underway.
Besides the fact that the criteria for diagnosing dysplasia are ill defined, another serious problem exists. A tissue specimen from a biopsy may not be representative of the whole lesion.
Medical Care
The objective of care is to detect and to prevent malignant change. The presence of the white plaque alone does not require treatment.
- Several management regimens have been suggested; however, no large trials have shown a definitive, reliable treatment. No evidence base exists on which to reliably recommend treatment. Indeed, current evidence suggests that no treatment is of reliable benefit.
- Possible courses of action include the following:
- Wait and watch
- Medical therapies (eg, anti-inflammatory agents, vitamins, cytotoxic agents)
- Surgical removal (eg, scalpel, laser, cryoprobe, electrosurgery, photodynamic therapy)
- Patients should avoid any causal factor, such as use of tobacco and alcohol. Leukoplakias can regress under these circumstances.
- Any degree of dysplasia in a lesion at a high-risk site must be taken seriously and the lesion should be removed.
- Occasionally, patients are treated by photodynamic therapy or topical cytotoxic agents.
- Patients should be examined regularly, probably at 3- to 6-month intervals.
Surgical Care
Management of leukoplakias is far from satisfactory, and no large trials offer guidance as to the most reliable treatment. Surgical removal of leukoplakia seems one reasonable option. Some experts surgically remove these lesions with scalpel, laser, or cryoprobe. Laser excision is preferred to fulguration. Others point out the possible aggravation of dysplasia caused by such operative intervention and that surgical removal of aneuploidic lesions does not improve mortality rates.
Diet
A diet rich in fresh fruits and vegetables may help prevent cancer.
Retinoids are currently being investigated as a possible treatment modality. They appear to be very effective but can have severe adverse effects on liver function and may cause teratogenicity. Their beneficial effect appears to last only during the treatment.
Drug Category: Retinoids
These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes and may reduce the potential for malignant degeneration. They modulate keratinocyte differentiation. They have been shown to reduce the risk of skin cancer formation in patients who have undergone renal transplantation.
| Drug Name | Isotretinoin (Accutane) |
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| Description | Oral agent that treats serious dermatologic conditions. Synthetic 13-cis isomer of the naturally occurring tretinoin (trans-retinoic acid). Both agents are structurally related to vitamin A. In acne, its activity includes reduction in sebaceous gland activity, modification of keratinocytic adhesion, and anti-inflammatory actions.
If used to treat acne, at least 8 wk should be allowed between courses of treatment if re-treatment is indicated (because of possible continued improvement).
Prescriber and patient must enroll in FDA-sponsored iPledge system to receive this medication. |
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| Adult Dose | 500 mcg/kg PO qd with food for 4 wk |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; pregnancy and breastfeeding |
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| Interactions | Toxicity may occur with vitamin A coadministration; pseudotumor cerebri or papilledema may occur when coadministered with tetracyclines; may reduce plasma levels of carbamazepine; alcohol may increase toxicity; topical agents that are drying and/or irritating may potentiate cutaneous adverse effects |
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| Pregnancy | X - Contraindicated in pregnancy
|
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| Precautions | If possible, avoid in women of childbearing age; if used (only for severe acne), the patient must be using 2 forms of birth control 1 mo before, during, and 1 mo after treatment (blood donors taking this drug should not donate blood during treatment and for 1 mo after this treatment has been stopped); may decrease night vision; hepatitis may occur; occasionally, exaggerated healing response of acne lesions (excessive granulation with crusting) may occur; transient exacerbation of acne may occur during initial period of treatment requiring reduction of dose and/or systemic corticosteroids; patients with diabetes may experience problems in controlling blood sugar and plasma triglyceride concentrations while on isotretinoin; caution in patients with preexisting or family history of hypertriglyceridemia
Avoid exposure to UV light or sunlight until tolerance has been achieved; with prolonged use (especially in treatment for disorders of cornification), skeletal abnormalities, including diffuse interstitial skeletal hyperostosis in adults and premature closure of the epiphyses in children, may occur; rarely, depression and attempts of suicide have occurred while taking this drug; laboratory monitoring includes CBC count, fasting blood lipids, hepatic function tests, and bhCG (for pregnancy); comprehensive metabolic panel/SMA-12 and blood sugar level have also been suggested |
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Further Outpatient Care
- Examine patients with leukoplakias regularly at 3- to 6-month intervals.
- Detection of clinical changes, such as erosions or nodule formation, warrants a biopsy. An oral brush biopsy may be helpful in detecting dysplasia.
Deterrence/Prevention
- Counsel patients against tobacco use. The percentage of nonsmokers who develop malignancy in a leukoplakia is greater than the percentage of smokers who develop a malignancy in a leukoplakia; however, the condition is more common in smokers such that the overall number of malignancies that arise in leukoplakias is greater in smokers.
- Advise patients to avoid alcohol use.
- Advise patients to eat a diet high in fresh fruits and vegetables.
Complications
- Some leukoplakias are potentially malignant.
- Dysplasia currently appears to be the best predictor of malignant potential. As many as 25% of leukoplakias are dysplastic at the first visit.
- DNA ploidy studies may help predict outcomes.
- Malignant change appears to be more frequent among nonsmokers than among smokers.
- A poorer prognosis is noted in the following:
- Nonsmokers
- Females
- Moderate or severe epithelial dysplasia
- Lesions in high-risk sites, such as the floor of the mouth
Prognosis
- Estimates of malignant transformation vary from 3-33% over a 10-year period. However, many innocuous leukoplakias are not always followed up in some centers, and the studies are often small.
- As many as 30% of leukoplakias can regress if habits are stopped.
Patient Education
- Patients should avoid alcohol, tobacco, and betel.
- Patients should consume a diet rich in fruits and vegetables.
- For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Cancer of the Mouth and Throat.
Medical/Legal Pitfalls
- Misdiagnosis is possible if adequate biopsy specimens are not taken.
- Early treatment is indicated, and complicating factors should be excluded.
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Leukoplakia, Oral excerpt Article Last Updated: Jul 11, 2006
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