Oral Leukoplakia 

Updated: Mar 13, 2019
Author: Christopher M Harris, MD, DMD; Chief Editor: Arlen D Meyers, MD, MBA 

Overview

Background

Oral leukoplakia (OL) is a white patch or plaque that cannot be rubbed off, cannot be characterized clinically or histologically as any other condition, and is not associated with any physical or chemical causative agent except tobacco. Therefore, a process of exclusion establishes the diagnosis of the disease. In general, the term leukoplakia implies only the clinical feature of a persistent, adherent white plaque; therefore, reserve the term for idiopathic lesions when investigations fail to reveal any cause. The term carries absolutely no histologic connotation, although, inevitably, some form of disturbance of the surface epithelium is characteristic.

Follow-up studies suggest that cancer is more likely to occur in individuals with idiopathic leukoplakia than in individuals who do not have this condition. Thus, idiopathic leukoplakia is considered a premalignant lesion.[1, 2]

Pathophysiology

The etiology of most cases of OL is unknown (idiopathic). In other cases, the initiation of the condition may depend on extrinsic local factors and/or intrinsic predisposing factors. Factors most frequently blamed for the development of idiopathic leukoplakia include tobacco use, alcohol consumption, chronic irritation, candidiasis, vitamin deficiency, endocrine disturbances, and possibly a virus.

Epidemiology

Frequency

International

OL occurs in fewer than 1% of individuals.

Mortality/Morbidity

OL is considered to be potentially malignant, with a transformation rate in various studies and locations that range from 0.6 to 20%.

A long-term follow-up study by Fan et al indicated that oral leukoplakia can increase the risk of esophageal squamous cell carcinoma (ESCC). The study, in which nearly 29,584 healthy adults were enrolled, found that 2924 persons in the study developed ESCC over a 28-year follow-up period; in adults aged 52 years or younger at baseline, the hazard ratio for the disease in those with leukoplakia was 1.31.[3]

Sex

OL is more common in men than in women, with a male-to-female ratio of 2:1.

Age

Most cases of OL occur in persons in their fifth to seventh decade of life. Approximately 80% of patients are older than 40 years.

 

Presentation

History

See the list below:

  • Oral leukoplakia (OL) manifests as patches that are bright white and sharply defined. The surfaces of the patches are slightly raised above the surrounding mucosa.

  • Individuals with OL are not symptomatic.

Physical

 

The following three stages of OL have been described:

  • The earliest lesion is nonpalpable, faintly translucent, and has white discoloration.
  • Next, localized or diffuse, slightly elevated plaques with an irregular outline develop. These lesions are opaque white and may have a fine, granular texture.
  • In some instances, the lesions progress to thickened, white lesions, showing induration, fissuring, and ulcer formation.

Clinically, OL falls into one of the following two main groups:

  • The most common are uniformly white plaques (homogenous OL) prevalent in the buccal mucosa, which usually have low premalignant potential.
  • Far more serious is speckled or verrucous leukoplakia, which has a stronger malignant potential than homogenous leukoplakia. Speckled leukoplakia consists of white flecks or fine nodules on an atrophic erythematous base. These lesions can be regarded as a combination of or a transition between leukoplakia and erythroplasia, which is flat or depressed below the level of the surrounding mucosal red patch, is uncommon in the mouth, and carries the highest risk of malignant transformation.

The following five clinical criteria demonstrate a particularly high risk of malignant change:

  • The verrucous type is considered high risk.
  • Erosion or ulceration within the lesion is highly suggestive of malignancy.
  • The presence of a nodule indicates malignant potential.
  • A lesion that is hard in its periphery is predictive of malignant change.
  • OL of the anterior floor of the mouth and undersurface of the tongue is strongly associated with malignant potential.

A literature review by Lyu et al focused on Chinese patients indicated that other risk factors for malignant transformation of OL include female gender, age over 50 years, and nonhomogeneity of OL.[4]

In all cases, the relative risk of malignant potential is determined by the presence of epithelial dysplasia upon histological examination.

Causes

See the list below:

  • In persons who smoke, the combustion end-products brought about by burning tobacco and heat (eg, tobacco tars and resins) are irritating substances capable of producing leukoplakic alterations of the oral mucosa. Years of heavy pipe, cigar, and cigarette smoking can lead to a characteristic type of benign keratosis in the hard palate, called stomatitis nicotina. Many investigators regard this lesion as simply an anatomic variant of leukoplakia. Numerous red dots due to the inflamed and dilated orifices of salivary gland ducts are apparent throughout the whitened palatal mucosa. Later, the mucosa becomes pale because of a slight increase in keratinization. In advanced cases, the palatal tissue is keratinized more heavily, and nodules appear that are related to hyperplasia of the underlying glands, retention of saliva, and fibrosis.

  • The use of alcohol has been suggested as a possible etiology because alcohol may irritate the mucosa. Persons who habitually consume considerable quantities of alcohol usually also smoke inveterately; therefore, establishing the effects of alcohol alone is difficult.

  • Malocclusion; chronic cheek biting; ill-fitting dentures; and sharp, broken-down teeth that constantly irritate the mucosa are considered extremely important in the etiology of OL.

  • Patients who have had syphilitic glossitis have a higher prevalence of OL than individuals with a nonsyphilitic background.

  • The presence of Candida albicans, a relatively common oral fungus, has been reported to be very frequently associated with OL.

  • Deficiency of vitamins A and B has been suggested as an inciting factor in the development of OL.

 

DDx

Diagnostic Considerations

These include the following:

  • Leukoedema

  • Lichen planus

  • Chemical burn

  • Morsicatio buccarum (habitual cheek biting)

  • Candidosis

  • Psoriasis

  • Lupus erythematosus

  • White sponge nevus

 

Workup

Laboratory Studies

Idiopathic lesions and dysplastic lesions do not have any specific clinical appearance. Therefore, in any case, the clinical appearance is not a guide to the underlying microscopic characteristics. A definitive diagnosis of oral leukoplakia is made when any etiological cause other than tobacco/areca nut use has been excluded and histopathology has not confirmed any other specific disorder.[5]

Procedures

Biopsy obtainment, repeated as necessary, is essential.

Histologic Findings

The plaque may show hyperorthokeratosis or hyperparakeratosis. The granular layer is often thickened and extremely prominent in cases of hyperorthokeratosis, but it is seldom observed in even severe cases of hyperparakeratosis. Acanthosis, which refers to the abnormal thickening of the prickle cell layer, may also be observed. Epithelial changes suggestive of premalignancy include the following:

  • Nuclear hyperchromatism

  • Loss of polarity

  • Increased number of mitotic figures

  • Nuclear pleomorphism

  • Altered nuclear-to-cytoplasmic ratio

  • Deep cell keratinization

  • Loss of differentiation

  • Loss of intercellular adherence

Yang et al analyzed the relationship between clinical features of OL using endoscopy with narrow-band imaging histopathology. They concluded that flexible endoscopy can be a successful tool for examining OL.[6]

Molecular markers that may indicate an increased likelihood of malignant transformation are (1) Mutations in the p53 gene, (2) Inappropriate expression of oncogenes (eg, cyclin D1), keratins, blood-group antigens and other cell-surface carbohydrates, and (3) DNA aneuploidy (when the amount of DNA is not an exact multiple of the diploid number). The latter emerges as one of the most promising prognostic indicators since oral cancer with poor survival consistently developed in human subjects with aneuploid dysplastic OL.[7, 8]

A study by Sakata et al indicated that a combination of low expression of the tumor suppressor SMAD4 and high stromal lymphocyte infiltration is predictive for the malignant transformation of OL.[9]

A study by von Zeidler et al suggested that reductions in the amount of epithelial cadherin (E-cadherin), a cellular adhesion protein, signal an increased risk of malignant transformation by OL. The investigators found that the amount of E-cadherin expressed in tissue differed between normal oral mucosa and low-risk OL, between low-risk and high-risk OL, and between high-risk OL and squamous cell carcinoma of the oral cavity with cervical lymph node metastasis.[10]

A study by Habiba et al indicated that expression of aldehyde dehydrogenase 1 and the transmembrane protein podoplanin are associated with a 3.02- and 2.62-fold increase, respectively, in the likelihood that OL will progress to oral cancer.[11]  In addition, a report by Grochau et al indicated that expression of podoplanin in OL correlates with the leukoplakia’s degree of dysplasia (as indicated by the lesion’s squamous intraepithelial neoplasia classification).[12] A study by Gissi et al also found evidence of a relationship between podoplanin expression and dysplasia in OL.[13]

 

Treatment

Medical Care

Surgical excision of oral leukoplakia (OL) may be considered. Frequent clinical observation accompanied by photographic records is recommended. Because of the unpredictable behavior of dysplastic lesions, immediately obtain a biopsy on any areas that are suggestive or that change in appearance.[14] Cryotherapy ablation and carbon dioxide laser ablation are also used.[15] The area heals rapidly, and apparently healthy mucosa is left behind. However, uncertainty remains regarding the risk of invasive carcinomas subsequently arising in sites previously treated.

Consultations

Consult an oral medicine specialist to evaluate etiologic factors and to determine the individualized treatment.

Diet

Discontinue the use of alcohol.

Activity

Physical activity is not restricted.

 

Medication

Medication Summary

Topical retinoids are ineffective. Systemic retinoids may be effective, but they have toxic effects. Studies that investigated the use of a high-dose induction followed by low-dose systemic isotretinoin report stabilization of the majority of lesions, a more effective response than beta-carotene in preventing malignant changes, and no toxicity.[16] Recently, studies report that beta-carotene produced sustained remissions in patients with oral leukoplakia (OL), with a durable response for at least 1 year.[17] Both of these drugs have been used in experimental trials and must be investigated in more depth.

 

Follow-up

Further Outpatient Care

Care includes monitoring the efficacy of surgical or systemic treatment with clinical observation.

Further Inpatient Care

Oral leukoplakia (OL) is managed exclusively in an outpatient setting.

Deterrence/Prevention

If etiologic factors can be determined, avoidance of these factors is recommended.

Prognosis

Approximately 10% of patients who develop OL have invasive carcinoma in the lesion (6%) or will develop carcinoma (4%).[18] Despite excision, small dysplastic lesions can be followed by multiple carcinomas and a fatal outcome. In addition, some dysplastic OL lesions may have a worse prognosis than isolated carcinomas without leukoplakia. However, the fact that many dysplastic OL lesions can regress spontaneously shows that the behavior of dysplastic lesions is unpredictable and that no reliable management protocol has been determined. Prolonged and close follow-up care is essential, but the prognosis may still be poor.

Patient Education

See the list below:

  • Patients must be aware that lesions may recur. They should be able to monitor the lesions and report any changes. They should maintain excellent oral hygiene.

  • For excellent patient education resources, visit eMedicineHealth's Cancer Center. Also, see eMedicineHealth's patient education article Cancer of the Mouth and Throat.