View source for User:Ian Furst/leukoplakia

==Definition==
<s>The word leukoplakia means "white patch",<ref name="Odell 2010" /> and is derived from the Greek words λευκός - "white"<ref name="Liddell & Scott">Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon. revised and augmented throughout by Sir Henry Stuart Jones. with the assistance of. Roderick McKenzie.'' Oxford: Clarendon Press.</ref> and πλάξ - "plate".<ref name="Liddell & Scott"/> Leukoplakia is a diagnosis of exclusion, meaning that what lesions are included depends upon what diagnoses are currently considered acceptable.<ref name="Soames 1999" /> Accepted definitions of leukoplakia have changed over time and are still controversial.<ref name="Tanaka 2011" /> It is possible that the definition will be further revised as new knowledge becomes available.<ref name="Soames 1999" />

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."<ref name="Soames 1999" /> There were however problems and confusion in applying this definition.<ref name="Soames 1999" /> 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.<ref name="Soames 1999" /> The second internal 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]].<ref name="Lodi 2006" />

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.<ref name="Odell 2010" /> It has been suggested that leukoplakia is an unhelpful term since there is so much inconsistency surrounding its use,<ref name="Odell 2010" /> and some clinicians now avoid using it at all.<ref name="Tanaka 2011" /></s>

<s>==Classification==
[[File:Leukoplakia.jpg|thumbnail|right|Leukoplakia in the lower labial sulcus.]]
[[File:Orale Leukoplakie.jpg|thumbnail|right|Leukoplakia of the soft palate]]
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.<ref name="Scully 2008" /> 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.<ref name="Højgaard 1991">{{cite journal|title=[Bladder leukoplakia].|journal=Ugeskrift for Laeger|date=Aug 26, 1991|volume=153|issue=35|pages=2408–9|pmid=1949238 |last1=Højgaard |first1=A. D. |last2=Jessen |first2=A. L. }}</ref><ref name="Coppi 1989">{{cite journal|last=Coppi|first=F|title=[Leukoplakia of the urinary tract].|journal=Archivio Italiano di Urologia, Nefrologia, Andrologia : Organo Ufficiale dell'Associazione per la Ricerca in Urologia = Urological, Nephrological, and Andrological Sciences|date=September 1989|volume=61|issue=3|pages=205–9|pmid=2529634}}</ref> Leukoplakia may also occur in the [[larynx]], possibly in association with [[gastro-esophageal reflux disease]].<ref name="Yamada 2009">{{cite book|last=edited by Tadataka Yamada ; associate editors, David H. Alpers ... [et al.]|title=Textbook of gastroenterology|year=2009|publisher=Blackwell Pub.|location=Chichester, West Sussex|isbn=978-1-4051-6911-0|pages=781, 850, 2705|edition=5th}}</ref> [[Oropharynx|Oropharyngeal]] leukoplakia is linked to the development of [[Esophageal cancer|esophageal squamous cell carcinoma]],<ref name="Yamada 2009" /> and sometimes this is associated with [[Diffuse nonepidermolytic palmoplantar keratoderma|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.<ref name="Yamada 2009" />

===Esophageal leukoplakia===
Leukoplakia of the esophagus is rare compared to oral leukoplakia.<!-- <ref name="Takubo 2007"> --> The relationship with [[esophageal cancer]] is unclear because the incidence of esophageal leukoplakia is so low.<!-- <ref name="Takubo 2007"> --> It usually appears as a small, nearly opaque white lesion that may resemble early esophageal squamous cell carcinoma.<!-- <ref name="Takubo 2007"> --> The histologic appearance is similar to oral leukoplakia, with hyperkeratosis and possible [[dysplasia]].<ref name="Takubo 2007">{{cite book|last=Takubo|first=Kaiyo|title=Pathology of the esophagus an atlas and textbook|year=2007|publisher=Springer Verlag|location=Tokyo|isbn=978-4-431-68616-3|pages=20, 21|edition=2nd}}</ref>

===Leukoplakia of the bladder===
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]].<!-- <ref name="Petrou 2013" /> --> The symptoms may include [[Frequent urination|frequency]], suprapubic pain (pain felt above the [[pubis (bone)|pubis]]), [[hematuria]] (blood in the urine), [[dysuria]] (difficult urination or pain during urination), [[Urinary urgency|urgency]], and [[urinary incontinence|urge incontinence]].<!-- <ref name="Petrou 2013" /> --> 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.<!-- <ref name="Petrou 2013" /> --> Leukoplakia of the bladder may undergo malignant transformation, so biopsy and long term follow up are usually indicated.<ref name="Petrou 2013">{{cite web|last=Petrou|first=Steven P|title=Leukoplakia of the Bladder|url=http://www.medscape.com/viewarticle/464488_print|publisher=Cliggott Publishing|accessdate=6 May 2013|coauthors=David M. Pinkstaff, Kevin J. Wu, Kenneth J. Bregg|date=November 2003}}</ref>

===Oral leukoplakia===
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====
Homogenous leukoplakia (also termed "thick leukoplakia")<ref name="Glick 2003" /> is usually well defined white patch of uniform, flat appearance and texture, although there may be superficial irregularities.<ref name="Glick 2003" /><ref name="Lodi 2006" /> Homogenous leukoplakia is usually slightly elevated compared to surrounding mucosa, and often has a fissured, wrinkled or corrugated surface texture,<ref name="Glick 2003" /> 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.<ref name="Glick 2003" /> When homogenous leukoplakia is [[palpation|palpated]], it may feel leathery, dry, or like cracked mud.<ref name="Glick 2003" />

====Non-homogenous leukoplakia====
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 ([[Cutaneous condition#Primary lesions|papular]]), [[Cutaneous condition#Primary lesions|nodular]] or [[wikt:exophytic|exophytic]].<ref name="Lodi 2006" /><ref name="Scully 2008">{{cite book|last=Scully C|title=Oral and maxillofacial medicine : the basis of diagnosis and treatment|year=2008|publisher=Churchill Livingstone|location=Edinburgh|isbn=978-0-443-06818-8|pages=113, 179, 211, 215–220|edition=2nd}}</ref> "Verrucous leukoplakia" (or "verruciform leukoplakia") is a descriptive term used for thick, white, papillary lesions.<!-- <ref name="Glick 2003" /> --> Verrucous leukoplakias are usually heavily keratinized and are often seen in elderly people.<!-- <ref name="Glick 2003" /> --> Some verrucous leukoplakias may have an exophytic growth pattern,<ref name="Glick 2003" /> 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.<ref name="Lodi 2006"/><!-- "Non-homogeneous leukoplakias carry a higher degree of risk of transformation when compared with the homogeneous variants." -->

=====Proliferative verrucous leukoplakia=====
Proliferative verrucous leukoplakia (PVL) is a recognized high risk subtype of non-homogenous leukoplakia.<ref name="Coulthard 2008" /> It is uncommon, and usually involves the buccal mucosa and the gingiva (the gums).<ref name="Treister 2010" /> This condition is characterized by (usually) extensive, papillary or verrucoid keratotic plaques that tends to slowly enlarge into adjacent mucosal sites.<ref name="Neville 2002" /><ref name="Glick 2003" /> An established PVL lesion is usually thick and exophytic (prominent), but initially it may be flat.<ref name="Treister 2010" /> 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.<ref name="Treister 2010">{{cite book|last=Bruch JM, Treister NS|title=Clinical oral medicine and pathology|year=2010|publisher=Humana Press|location=New York|isbn=978-1-60327-519-4|pages=121–122}}</ref> There is a very high risk of dysplasia and transformation to OSCC or to [[verrucous carcinoma]].<ref name="Glick 2003" />

=====Erythroleukoplakia=====
Erythroleukoplakia (also termed speckled leukoplakia, erythroleukoplasia or leukoerythroplasia) is a non-homogenous lesion of mixed white (keratotic) and red (atrophic) color. [[Erythroplakia]] 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.<ref name="Tyldesley 2003" /> 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,<ref name="Tyldesley 2003">{{cite book|last=Tyldesley WR, Field A, Longman L|title=Tyldesley's Oral medicine|year=2003|publisher=Oxford University Press|location=Oxford|isbn=0-19-263147-0|pages=33,36,38,39,43,46,106,111–117,121|edition=5th}}</ref> although any part of the mouth may be affected. Erythroleukoplakia and erythroplakia have a higher risk of malignant transformation than homogeneous leukoplakia.<ref name="Tyldesley 2003" />

====Sublingual keratosis====
Sometimes this term is used to describe leukoplakia of the [[floor of mouth]] or under the tongue.<ref name="Coulthard 2008" /> It is not universally accepted to be a distinct clinical entity from idiopathic leukoplakia generally,<ref name="Coulthard 2008" /> as it is distinguished from the latter by location only.<ref name="Odell 2010" /> Usually sublingual keratoses are bilateral and possesses a parallel-corrugated, wrinkled surface texture described as "ebbing tide".<ref name="Odell 2010" />

====Candidal leukoplakia====
Candidal leukoplakia is usually considered to be a largely historical synonym for a type of oral candidiasis, now more commonly termed [[oral candidiasis#(Chronic) hyperplastic candidiasis|chronic hyperplastic candidiasis]], rather than a subtype of true leukoplakia.<ref name="pmid12907694">{{cite journal |author=Sitheeque MA, Samaranayake LP |title=Chronic hyperplastic candidiasis/candidiasis (candidal leukoplakia) |journal=Crit. Rev. Oral Biol. Med. |volume=14 |issue=4 |pages=253–67 |year=2003 |pmid=12907694 |doi= 10.1177/154411130301400403|url=http://cro.sagepub.com/cgi/pmidlookup?view=long&pmid=12907694}}</ref> However, some sources use this term to describe leukoplakia lesions that become colonized secondarily by [[Candida (fungus)|Candida]] species, thereby distinguishing it from hyperplastic candidiasis.<ref name="Coulthard 2008">{{cite book|last=Coulthard P, Horner K, Sloan P, Theaker E|title=Master dentistry volume 1, oral and maxillofacial surgery, radiology, pathology and oral medicine|year=2008|publisher=Churchill Livingstone/Elsevier|location=Edinburgh|isbn=978-0-443-06896-6|pages=194–195|edition=2nd}}</ref>

====Oral hairy leukoplakia====
[[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.<ref name="Scully 2008" /> 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.<ref name="Coogan 2005">{{cite journal|title=Oral lesions in infection with human immunodeficiency virus.|journal=Bulletin of the World Health Organization|date=September 2005|volume=83|issue=9|pages=700–6|pmid=16211162|pmc=2626330 |last1=Coogan |first1=M. M. |last2=Greenspan |first2=J. |last3=Challacombe |first3=S. J. }}</ref> The appearance of the lesion often heralds the transition from HIV to [[acquired immunodeficiency syndrome]] (AIDS).<ref name="Coogan 2005" />

====Syphilitic leukoplakia====
This term refers to a white lesion associated with [[syphilis]], specifically in the tertiary stage of the infection.<ref name="Scully 2008" /> 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.<ref name="Coulthard 2008" /></s>

==Signs and symptoms==
Most cases of leukoplakia cause no symptoms,<ref name="Lodi 2006" /> but infrequently there may be discomfort or pain.<ref name="Glick 2003" /> The exact appearance of the lesion is very variable. Leukoplakia may be white, whitish yellow or grey.<ref name="Soames 1999" /> The size can range from a small area to lesions which involve a large area.<ref name="Soames 1999" /> The most common sites affected are the buccal mucosa, the labial mucosa and the [[alveolar mucosa]],<ref name="Tanaka 2011" /> although any mucosal surface in the mouth may be involved.<ref name="Glick 2003" /> The clinical appearance, including the surface texture and color, may be homogenous or non-homogenous (see: [[Leukoplakia#Classification|classification]]). Some signs are generally associated with a higher risk of malignant transformation (see: [[Leukoplakia#Prognosis|prognosis]]).

<s>==Causes==
The exact underlying cause of leukoplakia is largely unknown,<ref name="Neville 2002" /> but it is likely multifactorial, with the main factor being the use of tobacco.<ref name="Soames 1999" /> 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.<ref name="Soames 1999" /> This hides the normal pink-red color of mucosae (the result of underlying vasculature showing through the [[epithelium]]).<ref name="Neville 2002" /> 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]].<ref name="Soames 1999">{{cite book|last=Soames|first=JV|title=Oral pathology|year=1999|publisher=Oxford Univ. Press|location=Oxford [u.a.]|isbn=0-19-262894-1|pages=139–140, 144–151|edition=3. ed., [Nachdr.].|coauthors=Southam, J.C.}}</ref>

===Tobacco===
Tobacco smoking or chewing is the most common causative factor,<!-- <ref name="Soames 1999" /> --> with more than 80% of persons with leukoplakia having a positive smoking history.<!-- <ref name="Neville 2002" /> --> Smokers are much more likely to suffer from leukoplakia than non-smokers.<!-- <ref name="Neville 2002" /> --> 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.<ref name="Neville 2002" /> Other sources argue that there is no evidence for a direct causative link between smoking and oral leukoplakia.<ref name="Arduino 2013">{{cite journal|title=Urban legends series: oral leukoplakia.|journal=Oral Diseases|date=Jan 11, 2013|pmid=23379968|doi=10.1111/odi.12065|volume=19|issue=7|pages=642–59|last1=Arduino|first1=PG|last2=Bagan|first2=J.|last3=El-Naggar|first3=AK|last4=Carrozzo|first4=M.}}</ref> Cigarette smoking may produce a diffuse leukoplakia of the buccal mucosa, lips, tongue and rarely the [[floor of mouth]].<ref name="Soames 1999" /> Reverse smoking, where the lit end of the cigarette is held in the mouth is also associated with mucosal changes.<!-- <ref name="Soames 1999" /> --> 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".<!-- <ref name="Neville 2002" /> --> In the majority of persons, cessation triggers shrinkage or disappearance of the lesion, usually within the first year after stopping.<ref name="Neville 2002" /><ref name="Soames 1999" />

===Alcohol===
Although the [[synergy|synergistic effect]] of alcohol with smoking in the development of [[oral cancer]] is beyond doubt,<!-- <ref name="Neville 2002" />  --> there is no clear evidence that alcohol is involved in the development of leukoplakia, but it does appear to have some influence.<ref name="Soames 1999" /> 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.<ref name="Neville 2002" />

===Sanguinaria===
[[Sanguinaria]] (Bloodroot) is a herbal extract which is included in some [[toothpaste]]s and [[mouthwash]]es. Its use is strongly associated with development of leukoplakia, usually in the buccal sulcus.<ref>[http://www.aaomp.org/public/docs/leukoplakia.pdf Leukoplakia], (pdf format) hosted by the American Academy of Oral and Maxillofacial Pathology.  Page accessed on December 19, 2006.</ref> 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.<ref name="Neville 2002" />

===Ultraviolet radiation===
Ultraviolet radiation is believed to be a factor in the development of some leukoplakia lesions of the lower lip, where there is usually, additionally, an association with [[actinic cheilosis]].<ref name="Neville 2002" />

===Micro-organisms===
[[Candida (genus)|Candida]] in its [[pathogenic]] [[hyphae|hyphal]] form is occasionally seen in biopsies of idiopathic leukoplakia.<!-- <ref name="Soames 1999" /> --> It is debated whether candida infection is a primary cause of leukoplakia with or without dysplasia, or a superimposed (secondary) infection that occurs after the development of the lesion.<!-- <ref name="Soames 1999" /> --> It is known that Candida species thrive in altered tissues.<ref name="Soames 1999" /> Some leukoplakias with dysplasia reduce or disappear entirely following use of [[antifungal medication]].<ref name="Neville 2002" /> Smoking, which as discussed above can lead to the development of leukoplakia, can also promote oral candidiasis.<ref name="Neville 2002" /> Candida in association with leukoplakia should not be confused with white patches which are primarily caused by candida infection, such as chronic hyperplastic candidiasis ("candidal leukoplakia").<ref name="Coulthard 2008" />

The involvement of viruses in the formation of some oral white lesions is well established, e.g. Epstein-Barr virus in oral hairy leukoplakia (which is not a true leukoplakia). [[Human papilloma virus]] (HPV), especially HPV 16 and 18,<ref name="Neville 2002" /> is sometimes found in areas of leukoplakia, however since this virus can be coincidentally found on normal, healthy mucosal surfaces in the mouth, it is unknown if this virus is involved in the development of some leukoplakias.<ref name="Soames 1999" /> ''[[In vitro]] ''experimentation has demonstrated that HPV 16 is capable of inducing dysplastic changes in previously normal [[squamous epithelium]].<ref name="Neville 2002" />

===Epithelial atrophy===
Leukoplakia is more likely to develop in areas of epithelial [[atrophy]]. Conditions associated with mucosal atrophy include iron deficiency, some vitamin deficiencies, [[oral submucous fibrosis]], syphilis and [[sideropenic dysphagia]].<ref name="Soames 1999" />

===Tumor suppressor genes - p53===

[[Tumor suppressor gene]]s are genes involved in the regulation of normal cell turnover and [[apoptosis]] (programmed cell death).<ref name="Soames 1999" /> One of the most studied tumor suppressor genes is [[p53]], which is found on the short arm of chromosome 7. [[Mutation]] of p53 can disrupt its regulatory function and lead to uncontrolled cell growth.<ref name="Soames 1999" /> 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.<ref name="Soames 1999" />

===Trauma===
Another very common cause of white patches in the mouth is frictional or irritational trauma leading to keratosis. Examples include [[nicotine stomatitis]], which is keratosis in response to heat from tobacco smoking (rather than a response to the [[carcinogen]]s in tobacco smoke).<!-- <ref name="Neville 2002" /> --> The risk of malignant transformation is similar to normal mucosa.<!-- <ref name="Neville 2002" /> --> Mechanical trauma, e.g. caused by a sharp edge on a denture, or a broken tooth, may cause white patches which appear very similar to leukoplakia.<!-- <ref name="Neville 2002" /> --> However, these white patches represent a normal hyperkeratotic reaction, similar to a [[callus]] on the skin, and will resolve when the cause is removed.<ref name="Neville 2002" /> Where there is a demonstrable cause such as mechanical or thermal trauma, the term idiopathic leukoplakia should not be used.</s>

==Diagnosis==

<s>===Differential diagnosis of an oral white patch===
{| class="wikitable" style="float:right; width:350px;"
|-
! Cause !! Diagnosis
|-
| Normal anatomic variation || [[Fordyce's spot]]s (Fordyce's granules)
|-
| rowspan="7"|Developmental || [[White sponge nevus]]
|- 
| [[Leukoedema]] 
|-
| [[Pachyonychia congenita]]
|-
| [[Dyskeratosis congenita]]
|-
| [[Diffuse nonepidermolytic palmoplantar keratoderma|Tylosis]]
|-
| [[Hereditary benign intraepithelial dyskeratosis]]
|-
| [[Darier's disease]] (follicular keratosis)
|-
| rowspan="2"| Traumatic || Frictional keratosis (e.g. [[morsicatio buccarum]], [[Linea alba (cheek)|linea alba]], [[Factitious disorder|factitious injury]])
|-
| Chemical burn
|-
| rowspan="3"| Infective || [[Oral candidiasis]] 
|-
| [[Oral hairy leukoplakia]]
|-
| Syphlytic leukoplakia
|-
| rowspan="3"| Immunologic || [[Lichen planus]]
|-
| Lichenoid reaction (e.g. [[Lupus erythematosus]], [[Graft versus host disease]], [[Drug-induced lichenoid reaction]])
|-
| [[Psoriasis]]
|-
| rowspan="3"|Idiopathic and smoking related || Leukoplakia
|-
| [[Smoker's keratosis]] (Stomatitis nicotina)
|-
| Others e.g. Tobacco pouch keratosis, smokeless tobacco keratosis
|-
| rowspan="2"| Neoplastic || Oral [[squamous cell carcinoma]]
|-
| [[Carcinoma in situ]]
|-
| rowspan="2"| Other || Oral keratosis of [[renal failure]]
|-
| Skin graft
|}
There are many known conditions which present with a white lesion of the oral mucosa, but the majority of oral white patches have no known cause.<ref name="Odell 2010" /> 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.<ref name="Odell 2010" /> For this reason oral white patches are sometimes generally described as keratoses, although a minority of oral white lesions are not related to hyperkeratosis, e.g. epithelial [[necrosis]] and ulceration caused by a chemical burn (see: [[Oral ulceration#Chemical injury]]).<ref name="Odell 2010" /> In keratosis, the thickened keratin layer absorbs water from saliva in the mouth and appears white in comparison with normal mucosa. Normal oral mucosa is a red-pink color due the underlying vasculature in the [[lamina propria]] showing through the thin layer of epithelium. Melanin produced in the oral mucosa also influences the color, with a darker appearance being created by higher levels of melanin in the tissues (associated with racial/physiologic pigmentation, or with disorders causing melanin overproduction such as [[Addison's disease]]).<ref name="Soames 1999" /> Other endogenous pigments can be overproduced to influence the color, e.g. [[bilirubin]] in [[hyperbilirubinemia]] or [[hemosiderin]] in [[hemochromatosis]], or exogenous pigments such as heavy metals can be introduced into the mucosa, e.g. in an [[amalgam tattoo]].

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).<ref name="Odell 2010" /><ref name="Soames 1999" /><ref name="Terézhalmy 2009">{{cite book|last=Terézhalmy GT, Huber MA, Jones AC, Sankar V, Noujeim M|title=Physical evaluation in dental practice|year=2009|publisher=Wiley-Blackwell|location=Ames, Iowa|isbn=978-0-8138-2131-3|pages=170, 171|edition=Ed. 1st.}}</ref><ref name="Cawson 2002">{{cite book|last=Cawson RA, Odell EW, Porter S.|title=Cawsonś essentials of oral pathology and oral medicine.|year=2002|publisher=Churchill Livingstone|location=Edinburgh|isbn=0-443-07106-3|pages=221–238|edition=7th}}</ref>

Leukoplakia cannot be rubbed off the mucosa,<ref name="Petersen 2005" /> 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.<ref name="Terézhalmy 2009" /> Morsicatio buccarum and [[Linea alba (cheek)|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.</s>

<s>===Biopsy===
[[File:Cheekcells stained.jpg|thumbnail|left|Microscopic examination of [[keratinocyte]]s scraped from the buccal mucosa]]
Tissue [[biopsy]] is usually indicated<ref name="Scully 2000">{{cite journal|title=ABC of oral health. Swellings and red, white, and pigmented lesions.|journal=BMJ (Clinical Research Ed.)|date=Jul 22, 2000|volume=321|issue=7255|pages=225–8|pmid=10903660|pmc=1118223|last1=Scully|first1=C.|last2=Porter|first2=S.|doi=10.1136/bmj.321.7255.225}}</ref> to rule out other causes of white patches and also to enable a detailed [[histology|histologic]] examination to grade the presence of any epithelial dysplasia. This is an indicator of malignant potential and usually determines the management and recall interval. The sites of a leukoplakia lesion that are preferentially biopsied are the areas that show [[induration]] (hardening) and [[erythroplasia]] (redness), and erosive or [[mouth ulcer|ulcerated]] areas. These areas are more likely to show any dysplasia than homogenous white areas.<ref name="Scully 2000"/>

[[Exfoliative cytology#Cell collection|Brush biopsy/exfoliative cytology]] is an alternative to incisional biopsy,<ref name="Scully 2000" /> where a stiff brush is scraped against the lining of the mouth to remove a sample of cells. This is then made into a smear which can be examined microscopically. Sometimes the biopsy site can be selected with adjunct methods which aim to highlight areas of dysplasia. [[Toluidine blue]] staining, where the dye is preferentially retained by dysplastic tissue, is sometimes used, but there is high [[false positive]] rate.<ref name="Odell 2010" /> Other methods involve the use of illuminescence, relying on either the property of normal autoflorescent molecules in mucosa such as [[collagen]] and keratin which is lost from areas of dysplasia or carcinoma under blue light, or by initially staining of the mucosa with toluidine blue or dilute acetic acid and examination under white light.<ref name="Odell 2010" /></s>

<s>===Histologic appearance===
Leukoplakia has a wide range of possible histologic appearances. The degree of hyperkeratosis, epithelial thickness ([[acanthosis]]/[[wikt:atrohpy|atrohpy]]), dysplasia and inflammatory cell [[Infiltration (medical)|infiltration]] in the underlying lamina propria are variable.<ref name="Soames 1999" /> In mucous membranes, hyperkeratosis can be defined as "an increase in the thickness of the keratin layer of the epithelium, or the presence of such a layer in a site where none would normally be expected."<ref name="Tyldesley 2003" /> In leukoplakia, the hyperkeratosis varies in thickness, and may be either ortho- or para-keratosis, (depending upon whether [[Cell nucleus|cell nuclei]] are lost or retained in the superficial layers respectively), or a mixture of both in different areas of the lesion.<ref name="Soames 1999" /><ref name="Cawson 2002" />

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.<ref name="Neville 2002" /> The transition between the lesion and normal surrounding mucosa may be well demarcated, or poorly defined.<!-- <ref name="Soames 1999" />  --> Melanin, a pigment naturally produced in oral mucosa, can leak from cells and give a grey color to some leukoplakia lesions.<ref name="Soames 1999" />

Hyperkeratosis and altered epithelial thickness may be the only histologic features of a leukoplakia lesion, but some show dysplasia. The word dyspalsia 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.<ref name="Odell 2010" /> When dysplasia is present, there is generally an inflammatory cell infiltration in the lamina propria.<ref name="Cawson 2002" /> The following are commonly cited as being possible features of [[epithelial dysplasia]] in leukoplakia specimens:<ref name="Odell 2010" /><ref name="Soames 1999" />

* Cellular [[pleomorphism (cytology)|pleomorphism]], in which cells are of abnormal and different shapes.
* [[Nuclear atypia]], in which the [[cell nucleus|nuclei]] of cells varies in size, any may be [[NC ratio|increased in size relative to the cytoplasm]], shape, and may [[Hyperchromasia|stain more intensely]]. There may also be more prominent [[nucleolus|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 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 peg]]s 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.<ref name="Kerawala 2010">{{cite book|last=Kerawala C, Newlands C (editors)|title=Oral and maxillofacial surgery|year=2010|publisher=Oxford University Press|location=Oxford|isbn=978-0-19-920483-0|pages=422–424}}</ref> 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.</s>

==Treatment==
<S>A systematic review found that no treatments commonly used for leukoplakia have been shown to be effective in preventing malignant transformation.<!-- <ref name="Lodi 2006" /> --> Some treatments may lead to healing of leukoplakia, but do not prevent relapse of the lesion or maliginant change.<ref name="Lodi 2006" /> 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,<ref name="Terézhalmy 2009" />  and also involves long term review of the lesion,<ref name="Terézhalmy 2009" /> to detect any malignant change early and thereby improve the prognosis significantly.

===Removal of possible 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.<!-- <ref name="Odell 2010" /> --> Some clinicians use clinical photographs of the lesion to help demonstrate any changes between visits.<!-- <ref name="Odell 2010" /> --> Watchful waiting does not rule out the possibility of repeated biopsies.<ref name="Odell 2010" /> If the lesion changes in appearance repeat biopsies are especially indicated.<ref name="Glick 2003" /> 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.<ref name="Odell 2010" />

===Surgical removal===
Surgical removal of the lesion is the first choice of treatment for many clinicians.<!-- <ref name="Lodi 2006" /> --> However, the efficacy of this treatment modality cannot be assessed due to insufficient available evidence.<ref name="Lodi 2006" /> This can be carried out by traditional surgical excision with a scalpel, with lasers, or with [[Electrocautery#Electrocautery|eletrocoutery]] or [[cryotherapy]].<!-- <ref name="Lodi 2006" /> --><ref name="Terézhalmy 2009" /> Often if biopsy demonstrates moderate or severe dysplasia then the decision to excise them is taken more readily. Sometimes white patches are too large to remove completely and instead they are monitored closely. Even if the lesion is completely removed, long term review is still usually indicated since leukoplakia can recur, especially if predisposing factors such as smoking are not stopped.<ref name="Glick 2003" />

===Medications===
Many different [[Route of administration#Topical|topical]] and [[Route of administration#Local or systemic effect|systemic]] medications have been studied, including [[anti-inflammatory|anti-inflammatories]], [[antimycotic]]s (target Candida species), [[carotenoid]]s (precursors to [[vitamin A]], e.g. [[beta carotene]]), [[retinoid]]s (drugs similar to vitamin A), and [[cytotoxic]]s, but none have evidence that they prevent malignant transformation in an area of leukoplakia.<ref name="Lodi 2006" /> [[vitamin C|Vitamins C]] and [[vitamin E|E]] have also been studied with regards a therapy for leukoplakia.<ref name="Glick 2003" /> Some of this research is carried out based upon the hypothesis that [[antioxidant]] nutrients, [[vitamin]]s and cell growth suppressor proteins (e.g. p53) are antagonistic to [[oncogenesis]].<ref name="Glick 2003" /> High doses of retinoids may cause toxic effects.<ref name="Lodi 2006" /> Other treatments that have been studied include [[photodynamic therapy]].<ref name="Lodi 2006" /></S>

==Prognosis==
<S>The annual malignant transformation rate or leukoplakia rarely exceeds 1%,<ref name="Lodi 2006" /> i.e. the vast majority of oral leukoplakia lesions will remain benign.<ref name="Arduino 2013" /> 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.<ref name="Arduino 2013" /> It is also unpredictable to an extent if an area of leukoplakia will disappear, shrink or remain stable.<ref name="Feller 2012" /> 
* Presence and degree of dysplasia (mild, moderate or severe/[[carcinoma in situ]]). Dysplasia is the most important predictor of malignant change,<ref name="Odell 2010" /> and about 10% of leukoplakia lesions show dysplasia when biopsied.<ref name="Lodi 2006" /> 
* 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.<ref name="Odell 2010" /> Although these "high risk" sites are recognized, statistically, leukoplakia is more common on the buccal mucosa, alveolar mucosa, and the lower labial mucosa.<ref name="Tanaka 2011" /> Leukoplakia of the floor of the mouth and tongue accounts for over 90% of leukoplakias showing dysplasia or carcinoma on biopsy.<ref name="Glick 2003" />  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 that homogenous lekuoplakia.<ref name="Scully 2008" />
* Verrucous or nodular areas have a higher risk.<ref name="Odell 2010" />
* Although smoking increases risk of malignant transformation, smoking also causes many white patches with no dysplasia.<ref name="Odell 2010" /> This means that statistically, white patches in non smokers have a higher risk.<ref name="Glick 2003" /> 
* Older people with white patches are at higher risk.<ref name="Odell 2010" />
* Larger white patches are more likely to undergo malignant transformation than smaller lesions.<ref name="Odell 2010" />
* White patches which have been present for a long period of time have higher risk.<ref name="Odell 2010" />
* Persons with a positive family history of cancer in the mouth.<ref name="Odell 2010" />
* Candida infection in the presence of dysplasia has a small increased risk.<ref name="Odell 2010" />
* A change in the appearance of the white patch, apart from a change in the color, has a higher risk.<ref name="Odell 2010" /> Changes in the lesion such as becoming fixed to underlying tissues, [[mouth ulcer|ulceration]], cervical [[lymphadenopathy]] (enlargement of lymph nodes in the neck), and bone destruction may herald the appearance of malignancy.<ref name="Soames 1999" /> 
* White patches present in combination with other conditions that carry a higher risk (e.g. oral [[submucous fibrosis]]), are more likely to turn malignant.<ref name="Odell 2010" />
* Although overall, oral cancer is more common in males, females with white patches are at higher risk than men.<ref name="Odell 2010" /></S>

==Epidemiology==
<s>The prevalence of oral leukoplakia varies around the world, but generally speaking it is not an uncommon condition.<ref name="Lodi 2006" /> Reported prevalence estimates range from less than 1% to more than 5% in the general population.<ref name="Lodi 2006" /> Leukoplakia is therefore the most common premalignant lesion that occurs in the mouth.<ref name="Feller 2012">{{cite journal|title=Oral Leukoplakia as It Relates to HPV Infection: A Review.|journal=International Journal of Dentistry|date=2012|year=2012|volume=2012|pages=540561|pmid=22505902|pmc=3299253|doi=10.1155/2012/540561|last1=Feller|first1=L.|last2=Lemmer|first2=J.|doi-access=free}}</ref> Leukoplakia is more common in middle-aged and elderly males.<ref name="Tanaka 2011" /> The prevalence increases with increasing age.<ref name="Glick 2003" /> In areas of the world where smokeless tobacco use is common, there is a higher prevalence.<ref name="Glick 2003">{{cite book|last=Greenberg MS, Glick M|title=Burket's oral medicine diagnosis & treatment|year=2003|publisher=BC Decker|location=Hamilton, Ont.|isbn=1-55009-186-7|pages=87,88,90–93,101–105|edition=10th}}</ref></s>

==History==
<s>The term "leukoplakia" was coined in 1861 by Rokintansky, who used it to describe white lesions of the urinary tract.<ref name="Petrou 2013" />  In 1877 Schwimmer first used the term to describe an oral white lesion.<ref name="Tanaka 2011">{{cite journal|title=Oral Carcinogenesis and Oral Cancer Chemoprevention: A Review|journal=Pathology Research International|date=1 January 2011|volume=2011|doi=10.4061/2011/431246|pmc=3108384 |last1=Tanaka |first1=Takuji |last2=Tanaka |first2=Mayu |last3=Tanaka |first3=Takahiro |page=431246 |pmid=21660266 }}</ref> It is now thought that this white lesion on the tongue represented syphilitic glossitis,<ref name="Tanaka 2011" /> a condition not included in the modern definitions of oral leukoplakia. Since, the word leukoplakia has been incorporated into the names for several other oral lesions (e.g. "candidal leukoplakia", now more usually termed hyperplastic candidiasis).<ref name="Odell 2010" /> In 1930 it was shown experimentally that leukoplakia could be induced in rabbits that were subjected to tobacco smoke for 3 minutes per day.<ref>{{cite web|last=Roffo|first=AH|title=The carcinogenic effects of tobacco|url=http://www.who.int/bulletin/volumes/84/6/497.pdf|publisher=World Health Organization|accessdate=30 April 2013}}</ref> 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.<ref name="Petrou 2013" /> 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 describe an acquired condition in a female where dyskeratotic cells were present in the epithelia of the mouth and genitalia.<ref name="Weedon 2010">{{cite book|last=Weedon D|title=Weedon's skin pathology|year=2010|publisher=Churchill Livingstone/Elsevier|location=[Edinburgh]|isbn=978-0-7020-3485-5|edition=3rd|coauthors=Strutton G, Rubin AI}}</ref>{{rp|480}}<ref name="Andrews">{{cite book |author=James, William D.; Berger, Timothy G.; et al. |title=Andrews' Diseases of the Skin: Clinical Dermatology |publisher=Saunders Elsevier |location= |year=2006 |pages= |isbn=0-7216-2921-0 |oclc= |doi= |accessdate=}}</ref>{{rp|806}}</s>

== References ==
{{Reflist|2}}
{{Diseases of the skin and appendages by morphology}}
{{Oral pathology}}
{{Tumors of lip, oral cavity and pharynx}}
{{Diseases of the pelvis and genitals}}
{{Commons category|Leukoplakia}}

[[:Category:Oral neoplasia]]
[[:Category:Conditions of the mucous membranes]]
[[:Category:Oral pathology]]