Dermatologic Manifestations of Oral Leukoplakia 

Updated: Mar 10, 2022
Author: James J Sciubba, DMD, PhD; Chief Editor: William D James, MD 

Overview

Practice Essentials

The World Health Organization (WHO) first defined oral leukoplakia as a white patch or plaque that could not be characterized clinically or pathologically as any other disease; therefore, conditions including, but not limited to, lichen planus, candidiasis, and white sponge nevus were excluded. At a 1983 international seminar, the following definition was proposed:

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.

A more recent WHO workshop[1]  has amended the earlier WHO definition as follows: "The term leukoplakia should be used to recognize white plaques of questionable risk having excluded (other) known diseases or disorders that carry no risk for cancer.” It has also recommended abandoning the distinction between the terms "potentially malignant lesions" and "potentially malignant conditions" and to use the term "potentially malignant disorders" instead. Leukoplakia and erythroplakia are the most common potentially malignant disorders. These diagnoses are still defined by exclusion of other known white or red lesions. Not included in the discussion concerning leukoplakias are the rare inherited or genetically driven forms of oral white lesions, which include white sponge nevus, among others.[2]

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, congenital lesions (eg, white sponge nevus, dyskeratosis congenita, pachyonychia congenita), and frank carcinomas.

Oral leukoplakia was formerly often called "snuff-dipper's lesion" and is still sometimes referred to as "tobacco pouch keratosis" in the literature.[3, 4]

Symptoms

Leukoplakias are white lesions that cannot be removed with a gauze swab. Leukoplakias are usually asymptomatic and are initially noticed by a dentist during a routine examination.

Diagnostics

Perform an oral lesional biopsy. Unfortunately, exclusion of dysplasia in a biopsy sample does not guarantee that elsewhere in the lesion there is not dysplasia or even carcinoma.

A number of adjunctive diagnostic aids can assist in the clinical assessment of oral mucosal pathology. These include oral brush biopsy, toluidine vital staining and various light-based detection systems (eg, VELscope), and oral spectroscopy. However, evidence of efficacy is lacking. A 2015 Cochrane review concludes that “none of the adjunctive tests can be recommended as a replacement for the currently used standard of a scalpel biopsy and histological assessment”.[5]

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. For suspicious oral leukoplakia, surgical removal is the gold standard treatment.[6]

Prognosis

Some leukoplakias culminate in oral squamous cell carcinoma (OSCC).[7, 8]  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.

Sundberg et al reviewed 180 oral leukoplakia patients who underwent surgical removal of the lesions. The total incidence of lesion recurrence was 45% after 4 years and 49% after 5 years. Among non-homogeneous oral leukoplakia lesions, 23 (56%) cases recurred. Among snuff-users, 8 (73%) cases recurred. The investigators concluded that having non-homogenous lesions and using tobacco snuff were risk factors for oral leukoplakia recurrence after surgical removal.[6]  

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 than the general population.

Advise patients to avoid alcohol use. Additionally, advise patients to eat a diet high in fresh fruits and vegetables.

Long-term monitoring

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.

Patient education

For patient education resources, see the Cancer and Tumors Center, as well as Cancer of the Mouth and Throat.

Pathophysiology

No etiologic factor can be identified for most persistent oral white plaques (ie, idiopathic leukoplakia), although most white lesions are benign frictional keratoses. The histopathologic features of the group of leukoplakias 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.

Yogesh and Aswath point out that deletion of the glutathione S-transferase mu 1 (GSTM1) gene, especially with homozygosity (GSTM1 null), is associated with increased oral squamous cell carcinoma. This genetic abnormality may partially account for varying oral carcinoma incidence among smokeless tobacco users with oral leukoplakia.[9]   

Dysplastic lesions do not have any specific clinical appearance; however, where erythroplakia is present as an additional clinical component, 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 and so-called "thin" 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.[10]

Epidemiology

Oral leukoplakia is uncommon, possibly occurring in less than 1% of adults, with worldwide, nation-by-nation prevalence varying widely, based on cultural and dietary factors.[11]  An increased prevalence is observed in communities and races with high tobacco use, such as Southeast Asia. Males have the highest incidence of leukoplakias, and leukoplakias are usually seen in adults older than 40 years.

 

Presentation

Physical Examination

Most leukoplakias are smooth, white plaques (homogeneous leukoplakias), as shown in the image below.

Homogeneous leukoplakia. Homogeneous leukoplakia.

Most leukoplakias occur on the lip, the buccal mucosae, or the gingivae.

Some leukoplakias are white and warty (verrucous leukoplakia), as shown in the image below.

Verrucous or nodular leukoplakia. Verrucous or nodular leukoplakia.

Some leukoplakias are mixed white and red lesions (erythroleukoplakias or speckled leukoplakias), as shown in the image below.

Erythroleukoplakia. Erythroleukoplakia.

Proliferative verrucous leukoplakia (PVL), the least common form of leukoplakia, is characterized by verruciform keratosis that are progressive and multifocal, exhibiting a high rate of recurrence and progression to carcinoma.

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. Note the image below.

Carcinoma referred to as a leukoplakia. Carcinoma referred to as a leukoplakia.

A practical clinical tool for evaluating oral mucosal lesions has recently been developed. This tool is based on the grading of general clinical observations on a color scheme that reflects an increasing spectrum of concerns (green to red, or no concern to serious concern).[12, 13] This tool is summarized in the table below, with the headers representing the green spectrum being “No Serious Concern”, the yellow being “Concern”, and the red being “Serious Concern”.

Table. Practical Clinical Tool for Evaluating Oral Mucosal Lesions (Open Table in a new window)

Issue

 

No Serious Concern

Concern: Consider Referral to Specialist if Clinician or Patient Concerned, Especially if Multiple Issues Apply

Serious Concern: Referral to a Specialist

Historical Features

Size

No change

No reduction in size, even after eliminating trauma to lesion after 10-14 days

Increasing size, even after eliminating trauma to lesion after 10-14 days

 

Chronology

Lesion heals

No resolution over brief observation period

Rapid symptom onset

Solitary lesion or change in one area of lesion

Lesion persisting 3 weeks or longer

Persistent ulceration

Persistent swelling

Loosening of a tooth

Nonhealing tooth extraction socket

 

Neurological

None

Lack of pain

Pain

Dysphagia

Odynophagia

Otalgia

Numbness/paresthesia

Speech or voice change

 

Weight

Normal

No weight loss

Weight loss

History

Lifestyle Habits

None

Tobacco consumption mild/moderate

Betel quid or khat consumption mild/moderate

Marijuana consumption mild/moderate

UV light exposure mild/moderate (lip surface exposure

Late-onset sexual debut

Few or moderate numbers of lifetime sexual partners

Tobacco consumption high

Betel quid or khat consumption high

Alcohol consumption high

Marijuana consumption mild/moderate

UV light exposure high

Early sexual debut

Numerous lifetime sexual partners

 

Medical History

Clear

Deficiencies of iron or vitamins A, C, or E

Diabetes

Discoid lupus erythematosus

Dyskeratosis congenita

Epidermolysis bullosa

Fanconi anemia

High-risk human papillomavirus infection Immune defects, including HIV/AIDS or chronic candidosis

Medications: Immunosuppressants, antihypertensives

Periodontitis, poor hygiene

Plummer-Vinson syndrome

Scleroderma

Xeroderma pigmentosum

Deficiencies of iron or vitamins A, C, or E

Diabetes

Discoid lupus erythematosus

Dyskeratosis congenita

Epidermolysis bullosa

Fanconi anemia

High-risk human papillomavirus infection

Immune defects, including HIV/AIDS or chronic candidosis

Medications: Immunosuppressants, antihypertensives

Periodontitis, poor hygiene

Plummer-Vinson syndrome

Scleroderma

Xeroderma pigmentosum

Examination and Imaging

Potentially Malignant Disorder

None

Leukoplakia

Lichen planus/lichenoid mucositis

Oral submucous fibrosis

Erythroplakia

Leukoplakia; speckled or verrucous

Lichen planus/lichenoid mucositis; unilateral

 

Lesion Features

Equivocal

White patch (leukoplakia)

Lichen/lichenoid

Oral submucous fibrosis

Red patch (erythroplakia)

Mixed red and white patch (erythroleukoplakia/speckled leukoplakia)

Granular surface

Rolled, elevated margins

Ulceration

Induration

 

Cervical Lymph Nodes

No enlargement

Possible enlargement

Enlarged, firm, fixed, nontender, asymmetric

 

Imaging

No abnormality

Any bone density change

Poorly defined, uncorticated, irregular radiolucency

Lamina dura loss

Teeth displaced and/or resorbed

Pathological fracture

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: This includes smoked (including reverse smoking—lit end retained within the mouth) and smokeless (use of snuff and chewing tobacco); chewing tobacco likely contributes to oral leukoplakia more than smoking. [14]
  • Alcohol
  • Use of areca (betel) nut preparations, khat (qat), and similar products [15, 16]
  • Infections (eg, candidosis, syphilis, Epstein-Barr virus infection): Epstein-Barr virus infection causes a separate and distinct non–premalignant lesion termed oral hairy leukoplakia.
  • Chemicals (eg, sanguinaria) [17, 18]
  • Ultraviolet radiation (eg, actinic cheilitis)
  • Immune defects: Leukoplakias appear to be more common in transplant patients.

In cases of proliferative verrucous leukoplakia, the above risk factors are frequently absent; high-frequency allelic loss and high-risk allelic profiles noted in such lesions probably account for high-risk progression to dysplasia and malignancy.[19]

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 and loss of heterozygosity (LOH) studies may help predict outcomes.[20, 21, 22] Malignant change appears to be more frequent among nonsmokers than among smokers.

A poorer prognosis is noted in the following[22, 23, 24] :

  • Nonsmokers
  • Females
  • Nonhomogenous appearance
  • Size larger than 200 mm
  • Moderate or severe epithelial dysplasia
  • LOH at 9p/3p and further increased risk if additional LOH at 4q and 17p
  • Lesions in high-risk sites, such as the floor of the mouth/tongue/soft palate
 

DDx

Differential Diagnoses

 

Workup

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 (LOH), and DNA ploidy as molecular markers are currently underway.[25] LOH on bands 3p and/or 9p, survivin expression, expression of matrix metalloproteinase (MMP)–9, and DNA content are potential markers for increased risk of progression from oral dysplasia to cancer.[26]

Aneuploidy is associated with increased risk of progression to squamous carcinoma.[20] Microarray analysis using reverse-transcriptase polymerase chain reaction shows candidate biomarkers in cases resulting in cancer formation.[27]  On the cellular level, Wagh et al studied 420 oral leukoplakia cases and found that the average numbers of micronuclei were 1.14 in the control group, 2.63 in the potentially malignant group, and 4.88 in the confirmed malignancy group.[28]

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. Latent or unsampled dysplasias or carcinomas may be missed.[29]

Molecular Findings

The driver of malignant change within oral mucosal tissues is related to complex genetic and epigenetic changes, as noted in many cancers. Chromosomal instability, including altered telomerase function, loss of heterozygosity, and levels of DNA aneuploidy, have been reported and can predict the progression of premalignant oral lesions. Of note, both aneuploid as well as diploid lesions may progress to malignancy, with large variability noted in such transformation.[30] In a 2013 study, there was a 43.5-47.1% rate of malignant progression of aneuploid lesions, although it must be stated that not all such aneuploid leukoplakias behave in such a manner.[31] In a study of oral premalignant conditions with brushed and biopsy samples, it was found that a loss of heterozygosity at chromosome 9p had a significant association with malignant transformation. In such cases, a corresponding and additional mutation in TP53 dictates long-term, strict follow up, and, with observable changes, within or adjacent to the leukoplakia, a new biopsy is recommended for further genetic analysis.[32] Finally, those cases of leukoplakia at high risk for malignant transformation have been associated with aberrant promoter methylation sequences involving several genes, with significantly greater numbers of methylated sequences in dysplastic leukoplakias compared with those without such characteristics.[33]

Among tobacco chewers, epidermal growth factor receptor (EGFR) and Wnt signaling pathway proteins have shown massive overexpression. Furthermore, cells that were structurally abnormal tended to overexpress these oncoproteins.[34]

 

Treatment

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.

Possible courses of action include the following:

  • Remove any precipitating factors

  • Medical therapies (eg, anti-inflammatory agents, vitamins, cytotoxic agents)[35]

  • Surgical removal (eg, scalpel, laser, cryoprobe, electrosurgery, photodynamic therapy).[36]

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. Given that even evidently nondysplastic lesions may still contain malignancy in up to 10%, surgical removal of the lesion is advocated. Occasionally, patients are treated by photodynamic therapy or topical cytotoxic agents, but the evidence for efficacy is slender. Patients should be examined regularly, probably at 3- to 6-month intervals.

Surgical Care

Management of leukoplakias is far from satisfactory,[37] 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.[29, 38] Others point out the possible aggravation of dysplasia caused by such operative intervention and that surgical removal of aneuploidic lesions does not necessarily improve mortality rates.[39]

 

Medication

Medication Summary

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. A review of the use of topical immunomodulating agents (isotretinoin gel, 0.1%) in modulating or controlling dysplasia has shown not proven such agents to be uniformly effective.[40]

Retinoid-like Agents

Class Summary

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.

Isotretinoin (Amnesteem, Claravis, Myorisan, Sotret)

Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a 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 weeks should be allowed between courses of treatment if re-treatment is indicated (because of possible continued improvement).

The prescriber and patient must enroll in FDA-sponsored iPledge system to receive this medication. It is difficult to prescribe for off-label use (nonacne), especially because the iPledge system does not allow use beyond a 5- to 6-month period.