Leukoplakia

Oral leukoplakia is a potentially malignant disorder affecting the oral mucosa. It is defined as "essentially an oral mucosal white lesion that cannot be considered as any other definable lesion." Oral leukoplakia is a white patch or plaque that develops in the oral cavity and is strongly associated with smoking.

Treatment recommendations depend on features of the lesion.[4] If abnormal cells are present or the lesion is small surgical removal is often recommended; otherwise close follow up at three to six month intervals may be sufficient.^[4] People are generally advised to stop smoking and limit the drinking of alcohol.^[3] In potentially half of cases leukoplakia will shrink with stopping smoking;^[5] however, if smoking is continued up to 66% of cases will become more white and thick.^[6] The percentage of people affected is estimated at 1–3%.^[4] Leukoplakia becomes more common with age, typically not occurring until after 30.^[4] Rates may be as high as 8% in men over the age of 70.^[6]

Classification

Leukoplakia could be classified as mucosal disease, and also as a premalignant condition. Although the white color in leukoplakia is a result of

Within the mouth, leukoplakia is sometimes further classified according to the site involved, e.g. leukoplakia buccalis (leukoplakia of the buccal mucosa) or leukoplakia lingualis (leukoplakia of the lingual mucosa). There are two main clinical variants of oral leukoplakia, namely homogeneous leukoplakia and non-homogeneous (heterogenous) leukoplakia, which are described below. The word leukoplakia is also included within the nomenclature of other oral conditions which present as white patches, however, these are specific diagnoses that are generally considered separate from leukoplakia, with the notable exception of proliferative verrucous leukoplakia, which is a recognized sub-type of leukoplakia.

Homogeneous leukoplakia

Homogeneous leukoplakia (also termed "thick leukoplakia")^[2] is usually well defined white patch of uniform, flat appearance and texture, although there may be superficial irregularities.^[2][9] Homogeneous leukoplakia is usually slightly elevated compared to surrounding mucosa, and often has a fissured, wrinkled or corrugated surface texture,^[2] with the texture generally consistent throughout the whole lesion. This term has no implications on the size of the lesion, which may be localized or extensive.^[2] When homogeneous leukoplakia is palpated, it may feel leathery, dry, or like cracked mud.^[2]

Non-homogeneous leukoplakia

Non-homogeneous leukoplakia is a lesion of non-uniform appearance. The color may be predominantly white or a mixed white and red. The surface texture is irregular compared to homogeneous leukoplakia, and may be flat (

Erythroleukoplakia (also termed speckled leukoplakia, erythroleukoplasia or leukoerythroplasia) is a non-homogeneous lesion of mixed white (keratotic) and red (atrophic) color.

Sometimes leukoplakia of the

Candidal leukoplakia is usually considered to be a largely historical synonym for a type of oral candidiasis, now more commonly termed chronic hyperplastic candidiasis, rather than a subtype of true leukoplakia.^[23] However, some sources use this term to refer to leukoplakia lesions that become colonized secondarily by Candida species, thereby distinguishing it from hyperplastic candidiasis.^[19]

Oral hairy leukoplakia

This term refers to a white lesion associated with syphilis, specifically in the tertiary stage of the infection.^[15] It is not considered to be a type of idiopathic leukoplakia, since the causative agent Treponema pallidum is known. It is now rare, but when syphilis was more common, this white patch usually appeared on the top surface of the tongue and carried a high risk of cancerous changes.^[19] It is unclear if this lesion was related to the condition itself or whether it was caused by the treatments for syphilis at the time.^[24]

Esophagus

Leukoplakia of the esophagus is rare compared to oral leukoplakia. The relationship with esophageal cancer is unclear because the incidence of esophageal leukoplakia is so low. It usually appears as a small, nearly opaque white lesion that may resemble early esophageal squamous cell carcinoma. The histologic appearance is similar to oral leukoplakia, with hyperkeratosis and possible dysplasia.^[25]

Bladder

In the context of lesions of the mucous membrane lining of the bladder, leukoplakia is a historic term for a visualized white patch which histologically represents keratinization in an area of

Ultraviolet radiation is believed to be a factor in the development of some leukoplakia lesions of the lower lip, usually in association with actinic cheilitis.^[1]

Micro-organisms

Tumor suppressor genes are genes involved in the regulation of normal cell turnover and apoptosis (programmed cell death).^[29] One of the most studied tumor suppressor genes is p53, which is found on the short arm of chromosome 17. Mutation of p53 can disrupt its regulatory function and lead to uncontrolled cell growth.^[29] Mutations of p53 have been demonstrated in the cells from areas of some leukoplakias, especially those with dysplasia and in individuals who smoke and drink heavily.^[29]

DNA damage

DNA damage was measured in oral leukoplakia patients using single cell gel electrophoresis (also called the “comet assay”) applied to peripheral blood samples. The level of DNA damage was found to increase in a stepwise manner from healthy controls, through patients with non-dysplastic epithelium to patients with varying grades of dysplasia.^[35] In another study, DNA damage, also measured by the comet assay, was found to be greater in oral leukoplakia and squamous-cell carcinoma than in control subjects.^[36]

Diagnosis

Definition

Leukoplakia is a diagnosis of exclusion, meaning that which lesions are included depends upon what diagnoses are currently considered acceptable.^[29] Accepted definitions of leukoplakia have changed over time and are still controversial.^[30] It is possible that the definition will be further revised as new knowledge becomes available.^[29] In 1984 an international symposium agreed upon the following definition: "a whitish patch or plaque, which cannot be characterized clinically or pathologically as any other disease, and is not associated with any physical or chemical agent except the use of tobacco."^[29] There were, however, problems and confusion in applying this definition.^[29] At a second international symposium held in 1994, it was argued that whilst tobacco was a likely causative factor in the development of leukoplakia, some white patches could be linked directly to the local effects of tobacco by virtue of their disappearance following smoking cessation, suggesting that this kind of white patch represents a reactive lesion to local tissue irritation rather than a lesion caused by carcinogens in cigarette smoke, and could be better termed to reflect this etiology, e.g. smokers' keratosis.^[29] The second international symposium, therefore, revised the definition of leukoplakia to: "a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion."

In the mouth, the current definition of oral leukoplakia adopted by the World Health Organization is "white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer".^[37] However, this definition is inconsistently applied in the medical literature, and some refer to any oral white patch as "leukoplakia".^[3]

The term has been incorrectly used for white patches of any cause (rather than specifically referring to idiopathic white patches) and also to refer only to white patches which have a risk of cancerous changes.^[3] It has been suggested that leukoplakia is an unhelpful term since there is so much inconsistency surrounding its use,^[3] and some clinicians now avoid using it at all.^[30]

Biopsy

Tissue

The epithelium may show hypertrophy (e.g. acanthosis) or atrophy. Red areas within leukoplakia represent atrophic or immature epithelium which has lost the ability to keratinize.[1] The transition between the lesion and normal surrounding mucosa may be well-demarcated, or poorly defined. Melanin, a pigment naturally produced in oral mucosa, can leak from cells and give a grey color to some leukoplakia lesions.^[29]

Hyperkeratosis and altered epithelial thickness may be the only histologic features of a leukoplakia lesion, but some show dysplasia. The word "dysplasia" generally means "abnormal growth", and specifically, in the context of oral red or white lesions, refers to microscopic changes ("cellular atypia") in the mucosa that indicate a risk of malignant transformation.^[3] When dysplasia is present, there is generally an inflammatory cell infiltration in the lamina propria.^[38] The following are commonly cited as being possible features of epithelial dysplasia in leukoplakia specimens:^[3][29]

• Cellular pleomorphism, in which cells are of abnormal and different shapes.
• stain more intensely. There may also be more prominent nucleoli
  .
• Increased number of cells seen undergoing mitosis, including both normal and abnormal mitoses. Abnormal mitosis may be abnormally located, e.g. occurring in suprabasal cells (cell layers more superficial to the basal cell layer) or of abnormal form, e.g. "tri-radiate mitoses" (a cell splitting into 3 daughter cells rather than only 2)
• Loss the normal organization of the epithelial layers. The distinction between the epithelial layers may be lost. Normally stratified squamous epithelium shows progressive changes in the form of cells from the basal to the superficial layers, with cells becoming more flat ("squames") towards the surface as a continuous maturation process. In dysplastic epithelium, cells may become vertically orientated rather than becoming flat towards the surface.
• There may be abnormal
  keratinization, where keratin is formed below the normal keratin layer. This can occur in individual cells or groups of cells, forming an intraepithelial keratin pearl
  . There may be an increase in the number of basal cells, and they may lose their cellular orientation (losing their polarity and long axis).
• Alteration of the normal epithelial-connective tissue architecture - the
  rete pegs
  may become "drop shaped". wider at their base than more superficially.

Generally, dysplasia is subjectively graded by pathologists into mild, moderate or severe dysplasia. This requires experience as it is a difficult skill to learn. It has been shown that there is high degree of inter-observer variation and poor reproducibility in how dysplasia is graded.[39] Severe dysplasia is synonymous with the term carcinoma in situ, denoting the presence of neoplastic cells which have not yet penetrated the basement membrane and invaded other tissues.

Differential diagnosis

There are many known conditions that present with a white lesion of the oral mucosa, but the majority of oral white patches have no known cause.^[3] These are termed leukoplakia once other likely possibilities have been ruled out. There are also few recognized subtypes of leukoplakia, described according to the clinical appearance of the lesion.

Almost all oral white patches are usually the result of keratosis.

Almost all white patches are benign, i.e. non-malignant. The differential diagnosis of a white lesion in the mouth can be considered according to a surgical sieve (see table).^{[3][29][40][38]}

Leukoplakia cannot be rubbed off the mucosa,^[14] distinguishing it readily from white patches such as pseudomembraneous candidiasis, where a white layer can be removed to reveal an erythematous, sometimes bleeding surface underneath. The white color associated with leukoedema disappears when the mucosa is stretched. A frictional keratosis will generally be adjacent to a sharp surface such as a broken tooth or rough area on a denture and will disappear when the causative factor is removed. Some have a suggested as general rule that any lesion that does not show signs of healing within 2 weeks should be biopsied.^[40] Morsicatio buccarum and linea alba are located at the level of the occlusal plane (the level at which the teeth meet). A chemical burn has a clear history of placing an aspirin tablet (or other caustic substance such as eugenol) against the mucosa in an attempt to relieve toothache. Developmental white patches usually are present from birth or become apparent earlier in life, whilst leukoplakia generally affects middle aged or elderly people. Other causes of white patches generally require pathologic examination of a biopsy specimen to distinguish with certainty from leukoplakia.

Management

A systematic review found that no treatments commonly used for leukoplakia have been shown to be effective in preventing malignant transformation. Some treatments may lead to healing of leukoplakia, but do not prevent relapse of the lesion or malignant change.^[9] Regardless of the treatment used, a diagnosis of leukoplakia almost always leads to a recommendation that possible causative factors such as smoking and alcohol consumption be stopped,^[40] and also involves long term review of the lesion,^[40] to detect any malignant change early and thereby improve the prognosis significantly.

Predisposing factors and review

Beyond advising smoking cessation, many clinicians will employ watchful waiting rather than intervene. Recommended recall intervals vary. One suggested program is every 3 months initially, and if there is no change in the lesion, then annual recall thereafter. Some clinicians use clinical photographs of the lesion to help demonstrate any changes between visits. Watchful waiting does not rule out the possibility of repeated biopsies.^[3] If the lesion changes in appearance repeat biopsies are especially indicated.^[2] Since smoking and alcohol consumption also places individuals at higher risk of tumors occurring in the respiratory tract and pharynx, "red flag" symptoms (e.g. hemoptysis - coughing blood) often trigger medical investigation by other specialties.^[3]

Surgery

Surgical removal of the lesion is the first choice of treatment for many clinicians. However, the efficacy of this treatment modality cannot be assessed due to insufficient available evidence.

The annual malignant transformation rate of leukoplakia rarely exceeds 1%,^[9] i.e. the vast majority of oral leukoplakia lesions will remain benign.^[32] A number of clinical and histopathologic features are associated with varying degrees of increased risk of malignant transformation, although other sources argue that there are no universally accepted and validated factors which can reliably predict malignant change.^[32] It is also unpredictable to an extent if an area of leukoplakia will disappear, shrink or remain stable.^[41]

• Presence and degree of dysplasia (mild, moderate or severe/carcinoma in situ). While the degree of dysplasia has been shown to be an important predictor of malignant change,^[3] many have challenged its use due to the low predictive value from the lack of objectivity of grading dysplasia.^[42][43][44] While 10% of leukoplakia lesions show dysplasia when biopsied,^[9] as many as 18% of oral lesions undergo malignant change in the absence of dysplasia.^[45]
• Leukoplakia located on the floor of the mouth, the posterior and lateral tongue, and the retromolar areas (the region behind the wisdom teeth) have higher risk, whereas white patches in areas such as the top surface of the tongue and the hard palate do not have significant risk.^[3] Although these "high risk" sites are recognized, statistically, leukoplakia is more common on the buccal mucosa, alveolar mucosa, and the lower labial mucosa.^[30] Leukoplakia of the floor of the mouth and tongue accounts for over 90% of leukoplakias showing dysplasia or carcinoma on biopsy.^[2] This is thought to be due to pooling of saliva in the lower part of the mouth, exposing these areas to more carcinogens held in suspension.
• Red lesions (erythroplasia) and mixed red and white lesions (erythroleukoplakia/"speckled leukoplakia") have a higher risk of malignant change than homogeneous leukoplakia.^[15]
• Verrucous or nodular areas have a higher risk.^[3]
• Although smoking increases risk of malignant transformation, smoking also causes many white patches with no dysplasia.^[3] This means that statistically, white patches in non-smokers have a higher risk.^[2]
• Older people with white patches are at higher risk.^[3]
• Larger white patches are more likely to undergo malignant transformation than smaller lesions.^[3]
• White patches which have been present for a long period of time have a higher risk.^[3]
• Persons with a positive family history of cancer in the mouth.^[3]
• Candida infection in the presence of dysplasia has a small increased risk.^[3]
• A change in the appearance of the white patch, apart from a change in the color, has a higher risk.^[3] Changes in the lesion such as becoming fixed to underlying tissues, ulceration, cervical lymphadenopathy (enlargement of lymph nodes in the neck), and bone destruction may herald the appearance of malignancy.^[29]
• White patches present in combination with other conditions that carry a higher risk (e.g. oral
  submucous fibrosis), are more likely to turn malignant.^[3]
• Although overall, oral cancer is more common in males, females with white patches are at higher risk than men.[3]

Epidemiology

The prevalence of oral leukoplakia varies around the world, but generally speaking it is not an uncommon condition.^[9] Reported prevalence estimates range from less than 1% to more than 5% in the general population.^[9] Leukoplakia is, therefore, the most common premalignant lesion that occurs in the mouth.^[41] Leukoplakia is more common in middle-aged and elderly males.^[30] The prevalence increases with increasing age.^[2] In areas of the world where smokeless tobacco use is common, there is a higher prevalence.^[2] In the Middle East region, the prevalence of leukoplakia is less than 1% (0.48%).^[46]

Etymology

The word leukoplakia means "white patch",^[3] and is derived from the Greek words λευκός - "white" and πλάξ - "plate".^[47]

History

The term leukoplakia was coined in 1861 by Karl Freiherr von Rokitansky, who used it to refer to white lesions of the urinary tract.^[26] In 1877, Schwimmer first used the term for an oral white lesion.^[30] It is now thought that this white lesion on the tongue represented syphilitic glossitis,^[30] a condition not included in the modern definitions of oral leukoplakia. Since then, the word leukoplakia has been incorporated into the names for several other oral lesions (e.g. candidal leukoplakia, now more usually termed hyperplastic candidiasis).^[3] In 1930, it was shown experimentally that leukoplakia could be induced in rabbits that were subjected to tobacco smoke for 3 minutes per day.^[48] According to one source from 1961, leukoplakia can occur on multiple different mucous membranes of the body, including in the urinary tract, rectum, vagina, uterus, vulva, paranasal sinuses, gallbladder, esophagus, eardrums, and pharynx.^[26] Generally, oral leukoplakia is the only context where the term is in common usage in modern medicine. In 1988, a case report used the term acquired dyskeratotic leukoplakia to refer to an acquired condition in a female where dyskeratotic cells were present in the epithelia of the mouth and genitalia.^{[49]: 480 [31]: 806}

References

External links

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