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Oral leukoplakia on the buccal mucosa. Classification and external resources Specialty otolaryngologist [*] ICD- 10 K13.2, N48.0, N88.0, N89.4, N90.4 ICD- 9-CM 528.6, 530.83, 607.0, 622.2, 623.1, 624.0 DiseasesDB 7438 MedlinePlus 001046 Patient UK Leukoplakia MeSH D007971 [ edit on Wikidata] Leukoplakia (also termed leucoplakia, [1] leukokeratosis, [1] leukoplasia, [1] idiopathic leukoplakia, [2] idiopathic keratosis, [3] or idiopathic white patch), [3] normally refers to a condition where areas of keratosis appear as firmly attached white patches on the mucous membranes of the oral cavity, although the term is sometimes used for white patches of other gastrointestinal tract mucosal sites, or mucosal surfaces of the urinary tract and genitals. [4] [5] Leukoplakia in the mouth ( oral leukoplakia), is defined as a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion. [6] However, this definition is inconsistently applied, and some refer to any oral white patch as leukoplakia.

[3] Leukoplakia is a descriptive clinical term that is only correctly used once all other possible causes have been ruled out (a diagnosis of exclusion). [3] As such, leukoplakia is not a specific disease entity, and the clinical and histologic appearance are variable, i.e. the term has no specific histologic implications.

[7] Leukoplakia may be confused with other common causes of white patches in the mouth, such as oral candidiasis or lichen planus. The lesions of leukoplakia cannot be rubbed off, [8] as would be the case in pseudomembraneous candidiasis (oral thrush). Oral leukoplakia more commonly occurs in those who smoke, [1] but often the cause is unknown (hence the name idiopathic leukoplakia). [6] Chewing tobacco is also associated with this type of lesion. [9] Leukoplakia is a premalignant lesion, i.e.

a morphologically altered tissue in which cancer is more likely to occur than in its apparently normal counterpart. [6] The chance of transformation into oral squamous cell carcinoma (OSCC, a type of oral cancer) varies from almost 0% to about 20%, and this may occur over 1 – 30 years. [6] The vast majority of oral leukoplakias will not turn malignant, [10] however some subtypes hold greater risk than others. No interventions have been proven to reduce the risk of cancer developing in an area of leukoplakia, [6] but people are generally advised to stop smoking and limit alcohol consumption to reduce their risk.

[3] Sometimes the white patch will shrink and eventually disappear after stopping smoking, [11] but this may take up to a year. [7] In many cases, areas of leukoplakia will slowly expand, become more white and thicken if smoking is not stopped. [1] Management usually involves regular review of the lesion to detect any possible malignant change early, and thereby significantly improve the prognosis, which normally is relatively poor for OSCC. [6] Contents 1 Definition 2 Classification 2.1 Esophageal leukoplakia 2.2 Leukoplakia of the bladder 2.3 Oral leukoplakia 2.3.1 Homogenous leukoplakia 2.3.2 Non-homogenous leukoplakia Proliferative verrucous leukoplakia Erythroleukoplakia 2.3.3 Sublingual keratosis 2.3.4 Candidal leukoplakia 2.3.5 Oral hairy leukoplakia 2.3.6 Syphilitic leukoplakia 3 Signs and symptoms 4 Causes 4.1 Tobacco 4.2 Alcohol 4.3 Sanguinaria 4.4 Ultraviolet radiation 4.5 Micro-organisms 4.6 Epithelial atrophy 4.7 Tumor suppressor genes - p53 4.8 Trauma 5 Diagnosis 5.1 Differential diagnosis of an oral white patch 5.2 Biopsy 5.3 Histologic appearance 6 Treatment 6.1 Removal of possible predisposing factors and review 6.2 Surgical removal 6.3 Medications 7 Prognosis 8 Epidemiology 9 History 10 References Definition [ edit ] The word leukoplakia means white patch , [3] and is derived from the Greek words λευκός - white and πλάξ - plate. [12] Leukoplakia is a diagnosis of exclusion, meaning that which lesions are included depends upon what diagnoses are currently considered acceptable. [7] Accepted definitions of leukoplakia have changed over time and are still controversial.

[13] It is possible that the definition will be further revised as new knowledge becomes available. [7] 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. [7] There were however problems and confusion in applying this definition. [7] 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. [7] 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. This description is supported by the World Health Organization.

[6] The term has been incorrectly used to describe 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 malignant transformation. [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. [13] Classification [ edit ] Leukoplakia on the side of tongue Leukoplakia could be classified as mucosal disease, and also as a premalignant condition. Although the white color in leukoplakia is a result of hyperkeratosis (or acanthosis), similarly appearing white lesions that are caused by reactive keratosis ( smoker s keratosis or frictional keratoses e.g.

morsicatio buccarum) are not considered to be leukoplakias. [14] Leukoplakia could also be considered according to the affected site, e.g. oral leukoplakia, leukoplakia of the urinary tract, including bladder leukoplakia or leukoplakia of the penis, vulvae, cervix or vagina.

[15] [16] Leukoplakia may also occur in the larynx, possibly in association with gastro-esophageal reflux disease. [17] Oropharyngeal leukoplakia is linked to the development of esophageal squamous cell carcinoma, [17] and sometimes this is associated with tylosis, which is thickening of the skin on the palms and soles of the feet (see: Leukoplakia with tylosis and esophageal carcinoma). Dyskeratosis congenita may be associated with leukoplakia of the oral mucosa and of the anal mucosa. [17] Esophageal leukoplakia [ edit ] 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. [18] Leukoplakia of the bladder [ edit ] In the context of lesions of the mucous membrane lining of the bladder, leukoplakia is a historic term used to describe a visualized white patch which histologically represents keratinization in an area of squamous metaplasia. The symptoms may include frequency, suprapubic pain (pain felt above the pubis), hematuria (blood in the urine), dysuria (difficult urination or pain during urination), urgency, and urge incontinence. The white lesion may be seen during cystoscopy, where it appears as a whitish-gray or yellow lesion, on background of inflamed urothelium and there may be floating debris in the bladder.

Leukoplakia of the bladder may undergo malignant transformation, so biopsy and long term follow up are usually indicated. [19] Oral leukoplakia [ edit ] 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 homogenous leukoplakia and non-homogenous (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 which are generally considered separate from leukoplakia, with the notable exception of proliferative verrucous leukoplakia, which is a recognized sub-type of leukoplakia.

Homogenous leukoplakia [ edit ] Homogenous 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] [6] Homogenous 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 homogenous leukoplakia is palpated, it may feel leathery, dry, or like cracked mud. [2] Non-homogenous leukoplakia [ edit ] Non-homogenous 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 homogenous leukoplakia, and may be flat ( papular), nodular or exophytic. [6] [14] Verrucous leukoplakia (or verruciform leukoplakia ) is a descriptive term used for thick, white, papillary lesions. Verrucous leukoplakias are usually heavily keratinized and are often seen in elderly people.

Some verrucous leukoplakias may have an exophytic growth pattern, [2] and some may slowly invade surrounding mucosa, when the term proliferative verrucous leukoplakia may be used. Non-homogenous leukoplakias have a greater risk of malignant transformation than homogenous leukoplakias. [6] Proliferative verrucous leukoplakia [ edit ] Proliferative verrucous leukoplakia (PVL) is a recognized high risk subtype of non-homogenous leukoplakia.

[20] It is uncommon, and usually involves the buccal mucosa and the gingiva (the gums). [21] This condition is characterized by (usually) extensive, papillary or verrucoid keratotic plaques that tends to slowly enlarge into adjacent mucosal sites. [1] [2] An established PVL lesion is usually thick and exophytic (prominent), but initially it may be flat. [21] Smoking does not seem to be as strongly related as it is to leukoplakia generally, and another dissimilarity is the preponderance for women over 50. [21] There is a very high risk of dysplasia and transformation to OSCC or to verrucous carcinoma.

[2] Erythroleukoplakia [ edit ] Erythroleukoplakia ( speckled leukoplakia ), left commissure. Biopsy showed mild epithelial dysplasia and candida infection. Antifungal medication may turn this type of lesion into a homogenous leukoplakia (i.e. the red areas would disappear) Erythroleukoplakia (also termed speckled leukoplakia, erythroleukoplasia or leukoerythroplasia) is a non-homogenous lesion of mixed white (keratotic) and red (atrophic) color. Erythroplakia (erythroplasia) is an entirely red patch that cannot be attributed to any other cause. Erythroleukoplakia can therefore be considered a variant of either leukoplakia or erythroplakia since its appearance is midway between.

[22] Erythroleukoplakia frequently occurs on the buccal mucosa in the commisural area (just inside the cheek at the corners of the mouth) as a mixed lesion of white nodular patches on an erythematous background, [22] although any part of the mouth may be affected. Erythroleukoplakia and erythroplakia have a higher risk of malignant transformation than homogeneous leukoplakia. [22] Sublingual keratosis [ edit ] Homogenous leukoplakia in the floor of the mouth in a smoker. Biopsy showed hyperkeratosis Sometimes this term is used to describe leukoplakia of the floor of mouth or under the tongue.

[20] It is not universally accepted to be a distinct clinical entity from idiopathic leukoplakia generally, [20] as it is distinguished from the latter by location only. [3] Usually sublingual keratoses are bilateral and possesses a parallel-corrugated, wrinkled surface texture described as ebbing tide. [3] Candidal leukoplakia [ edit ] 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 describe leukoplakia lesions that become colonized secondarily by Candida species, thereby distinguishing it from hyperplastic candidiasis. [20] Oral hairy leukoplakia [ edit ] Oral hairy leukoplakia is a corrugated ( hairy ) white lesion on the sides of the tongue caused by opportunistic infection with Epstein-Barr virus on a systemic background of immunodeficiency, almost always human immunodeficiency virus (HIV) infection.

[14] This condition is not considered to be a true idiopathic leukoplakia since the causative agent has been identified. It is one of the most common oral lesions associated with HIV infection, along with pseudomembraneous candidiasis. [24] The appearance of the lesion often heralds the transition from HIV to acquired immunodeficiency syndrome (AIDS). [24] Syphilitic leukoplakia [ edit ] This term refers to a white lesion associated with syphilis, specifically in the tertiary stage of the infection.

[14] 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 malignant transformation. [20] 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. [25] Signs and symptoms [ edit ] Most cases of leukoplakia cause no symptoms, [6] but infrequently there may be discomfort or pain. [2] The exact appearance of the lesion is variable. Leukoplakia may be white, whitish yellow or grey.

[7] The size can range from a small area to much larger lesions. [7] The most common sites affected are the buccal mucosa, the labial mucosa and the alveolar mucosa, [13] although any mucosal surface in the mouth may be involved. [2] The clinical appearance, including the surface texture and color, may be homogenous or non-homogenous (see: classification). Some signs are generally associated with a higher risk of malignant transformation (see: prognosis). Causes [ edit ] The exact underlying cause of leukoplakia is largely unknown, [1] but it is likely multifactorial, with the main factor being the use of tobacco.

[7] Tobacco use and other suggested causes are discussed below. The mechanism of the white appearance is thickening of the keratin layer, called hyperkeratosis. The abnormal keratin appears white when it becomes hydrated by saliva, and light reflects off the surface evenly. [7] This hides the normal pink-red color of mucosae (the result of underlying vasculature showing through the epithelium). [1] A similar situation can be seen on areas of thick skin such as the soles of the feet or the fingers after prolonged immersion in water. Another possible mechanism is thickening of the stratum spinosum, called acanthosis.

[7] Tobacco [ edit ] Tobacco smoking or chewing is the most common causative factor, with more than 80% of persons with leukoplakia having a positive smoking history. Smokers are much more likely to suffer from leukoplakia than non-smokers. The size and number of leukoplakia lesions in an individual is also correlated with the level of smoking and how long the habit has lasted for. [1] Other sources argue that there is no evidence for a direct causative link between smoking and oral leukoplakia. [10] Cigarette smoking may produce a diffuse leukoplakia of the buccal mucosa, lips, tongue and rarely the floor of mouth.

[7] Reverse smoking, where the lit end of the cigarette is held in the mouth is also associated with mucosal changes. Tobacco chewing, e.g. betel leaf and areca nut, called paan, tends to produce a distinctive white patch in a buccal sulcus termed tobacco pouch keratosis. In the majority of persons, cessation triggers shrinkage or disappearance of the lesion, usually within the first year after stopping. [1] [7] Alcohol [ edit ] Although the synergistic effect of alcohol with smoking in the development of oral cancer is beyond doubt, there is no clear evidence that alcohol is involved in the development of leukoplakia, but it does appear to have some influence. [7] Excessive use of a high alcohol containing mouth wash (> 25%) may cause a grey plaque to form on the buccal mucosa, but these lesions are not considered true leukoplakia.

[1] Sanguinaria [ edit ] Sanguinaria (Bloodroot) is a herbal extract which is included in some toothpastes and mouthwashes. Its use is strongly associated with development of leukoplakia, usually in the buccal sulcus. [26] This type of leukoplakia has been termed sanguinaria associated keratosis and more than 80% of people with leukoplakia in the vestibule of the mouth have used this substance. Upon stopping contact with the causative substance, the lesions may persist for years.

Although this type of leukoplakia may show dysplasia, the potential for malignant transformation is unknown. [1] Ultraviolet radiation [ edit ] Ultraviolet radiation is believed to be a factor in the development of some

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