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Therapeutics in Dermatology
A reference textbook in dermatology
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White lesions of the mouth

28 January 2013, by RENAUD-VILMER C. , CAVELIER-BALLOY B. & RAGOT J.-P.

White lesions of the mucous membranes in the mouth (the term keratosis is no longer used because it relates to histology rather than being a clinical description) are primary lesions that are often linked to abnormal keratin production and this can have a number of causes. It is important that a diagnosis is made because it is possible that the lesions may be pre-cancerous in some cases and the diagnosis must always be backed up by histopathology investigations. The clinical examination will always look for associated skin lesions and lesions of any other mucous membranes (genital or anal). There are different clinical appearances: white papules smaller than 5 mm that are slightly raised; lace-like with a reticular patterns, plaques formed of papules joined together that are slightly raised; lesions that are visibly papillomatous with a verrucous (thickened and scaly) appearance. These lesions may be solitary or mutiple and they can be associated with erosive, atrophic, hypertrophic or nodular areas.

LEUKOPLAKIA

Leukoplakia is defined as a white lesion of the oral mucosa that cannot be rubbed off and which is not the oral localisation of a known disease. Tobacco use is the main cause of leukoplakia. Where a tobacco-related lesion is found depends on the way in which the user consumes tobacco. These lesions have a variable pattern of progression and a possible risk of malignant transformation assessed at 5 to 38%.

Tobacco-related leukoplakia can resolve when the patient gives up smoking. However, the epidemiology of leukoplakia of the oral mucosa overlaps with that of oral cancers in respect of age, sex, and tobacco use. They mainly develop in men, although recent studies have shown a significant growth in their occurrence in women. The average age is 50, but this is indisputably falling. 10% of oral cancers arise in patients who have previously presented oral leukoplakia. The length of time between discovering leukoplakia and it degenerating into cancer is on average ten years.

Associated factors: Alcohol abuse increases the action of tobacco. Other factors can be involved: poor hygiene, Candida albicans infection, consumption of areca nuts, mucosal atrophy in some chronic cases of anaemia, and vitamin deficiencies.

CLINICAL PRESENTATION

Leukoplakia lesions do not usually cause symptoms. The following are distinguished from one another:

– Homogenous leukoplakia. This is a smooth spongy whitish plaque with no underlying hardness. It is not painful and is usually discovered by chance.

– Non-homogenous leukoplakia. This lesion has an irregular surface, which can appear verrucous and may be associated with plaques of redness or erythroplakia (erythroleukoplakia), or even ulcers or nodules. These specific clinical characteristics point to lesions that carry a higher risk of developing into cancer.

Although there is some overlap between the clinical and histological findings, the clinical appearance alone is not enough to predict the underlying histology findings. Erythroleukoplakia lesions have a risk of transformation to cancer of between 28 and 38%, and in verrucous leukoplakia the risk is between 5 and 11%.

One or more biopsies will be a crucial part of the treatment.

HISTOPATHOLOGY

Leukoplakia lesions have common histologic characteristics: acanthosis associated with orthokeraosis or parakeratosis. These histological findings usually point to homogenous leukoplakia.

The presence of cellular atypia points to oral intraepithelial neoplsia (OIN). Currently, in terms of treating these lesions, only two grades are distinguished: mild OIN and moderate to severe OIN.

TREATMENT

Surgical excision is the standard treatment because it allows the whole lesion to be examined histologically. The lesion is removed in one piece following its outlines with a 1 - 3 mm margin extending to the depth of the muscle. The margin will be 5 mm from the outset in severe OIN.

For mild OIN, CO2 lasers appear to be an ideal treatment because they are harmless, the process is easy to carry out, and there are few side effects. It is tending to replace electrocoagulation, which can lead to painful and retractile scar tissue.

Cryotherapy produces excellent results but it can only be carried out by an experienced practitioner.

Radiotherapy is formally contraindicated for this kind of lesion.

The application of keratolytic agentsand the use of topical retinoids (13-cis-retinoic acid, 0.01% solution) applied on a daily basis can in some patients lead to leukoplakia shrinking if there are cellular atypia or only mild OIN.

Systemic administration of vitamin A and retinoids is no longer used due to very disappointing results (patients almost always relapsed on stopping treatment) and because they have considerable toxicity.

IMPROVING HYGIENE

Managing leukoplakia also involves local hygiene measures and general lifestyle changes: reduced alcohol intake, ensuring teeth are in good condition, having teeth and roots removed if they will not benefit from conservative treatment, getting rid of tartar above and below the gums, removal of any dental implants causing damage, reconstruction of teeth that are suitable for conservative treatment, and daily dental and oral hygiene routine.

POST-OPERATIVE MONITORING

Follow-up for treated and untreated leukoplakia must continue indefinitely, on at least an annual basis. Everything possible must be done to help patients stop using tobacco. If the lesions do not shrink, an excision-biopsy must be offered.

Even if the lesion is cured and tobacco use has been stopped this does not mean monitoring comes to an end. It should continue annually as there is a risk of relapse or new lesions.

WHITE LESIONS CAUSED BY DERMATOLOGICAL CONDITIONS

LICHEN PLANUS (LP)

Lichen planus is a chronic inflammatory disease of the skin and mucous membranes that affects 0.5 – 2% of the population. Isolated oral forms predominate making this one of the main conditions of the oral mucous membranes (accounting for 5% of consultations in medical stomatology).

 The treatment approach should take the clinical form into account, distinguishing the inactive form from other types (bullous-erosive, verrucous, or atrophic), as the risk of these forms transforming into cancer is unanimously agreed upon. The estimated risk of this transformation to cancer for all types of lichen planus combined seems to be in the region of 1%.

Causes

There are numerous theories about the cause of this condition: involvement of auto-immunity factors, genetic factors, the hepatitis C virus, an action caused by some medications, and metals used in some dental implants have all been suggested.

Clinical forms

Inactive form

This is a white lesion that can vary in its appearance, looking either lace -like with a reticular pattern, or a soft papule or plaque. It is mainly found in the back part of the cheek. It is discovered by chance or on diagnosis of lichen planus of the skin, or more rarely, due to a hypersensitivity reaction or tingling sensation on contact with certain foods.

Bullous-erosive forms

These forms usually present with large blisters that are quickly replaced by painful, irregularly shaped, bright red, shiny areas of erosion, with oedema at the centre.

Very often the usual lacy, ring-shaped LP patterns are found at the edges. At this stage the lesion causes pain, and there is discomfort on eating or carrying out usual dental and oral hygiene practices.

Localisation to the gingivae is common and it appears as wide, red plaques along the length of the attached gum (desquamative gingivitis). It must be differentiated from a manifestation of a blistering disease such as bullous pemphigoid. If a gingival location of erosive lesions is identified, localisation in the other mucous membranes (genital or anal) must be investigated.

Atrohic form

This generally develops in sites affected by bullous-erosive lesions inside the cheeks, but it can also appear on the dorsal of the tongue in the form of smooth plaques associated with loss of papillae. Verrucous bands appear on these plaques and lead to hollowed out fissures that tighten around the tongue giving it an atrophic appearance. Within the plaques of atrophy and verrucous bands, there may be suspicious areas of erythroplakia.

Hypertrophic or verrucous lichen planus

This consists of white, verrucous papules or plaques that generally develop in an area already affected by lichen planus papules or atrophy.

Histopathology

 Lichen planus has the following characteristic features: orthokeratosis or parakeratosis, regular hyperacanthosis with formation of apoptotic bodies, and a band of lymphocytic inflammatory infiltrate in contact with the basement membrane associated with exocytosis in the basal layers.

Treatment

Inactive, lacy-pattern lichen planus only requires monitoring. If small areas of inflammation, blistering and erosion, or verrucous lesions develop, then treatment is required. The main treatment is topical corticosteroids.

Topical treatments

– Topical corticosteroids are prescribed in the form of betamethasone 17-valerate (Buccobet®) tablets that are placed under the tongue. The dose varies from 8 to 10 tablets per day for courses of 10 to 15 days, with a reduced dose for a 10-day period once a positive effect has been seen. This is the only treatment that has been subject to randomised placebo-controlled clinical trials.

Other topical treatments may be used in erosive forms that do not respond to treatment: a Diprolene®/Orabase® mixture or a prepared mouthwash taken each morning and evening with one 20mg tablet of Solupred® (prednisolone) added. Ciclosporin as a mouthwash or applied topically and topical Protopic have been shown to have some effect on inflamed or ulcerative lesions but these treatments are not given over the long-term.

Hyperkeratotic lesions with no ulceration can be treated with a topical application of a retinoic acid-based treatment (Aberel®). However, its long-term usage has been disappointing, with lesions reappearing when treatment is stopped.

– Surgical removal must be offered for hyperkeratotic lesions that do not respond to treatment.

Systemic treatments

Oral corticosteroids (at a dose of 1.5 - 1 mg/kg) can be used in widespread bullous forms that do not respond to topical treatment, but corticosteroid dependence is very quickly seen, often from doses of 20 mg, as well as a worrying rebound phenomenon when it is discontinued, even when alternated with topical corticosteroids. This means that this treatment must be reserved for cases in which all other treatments have failed.

In isolated bullous-erosive forms, some stomatology specialists offer to inject a suspension of corticosteroids below the lesions using short, fine needles.

In hyperkeratotic forms, oral use of retinoids such as etretinate (Tigason®) or acitretin (Soriatane®) has been shown to be somewhat effective but they do not prevent relapse when treatment is stopped.

Additional treatments

When the gums are affected, there is often a secondary infection of the periodontium. In addition to the main treatment, this should be treated with an antibiotic such as Birodogyl®. On top of this, there may also be an oral fungal infection that will have to be treated. Metal dental crowns should, where possible, be replaced by porcelain crowns as they are safer. Spa therapies, such as those at Saint-Christau in the Aquitaine region of France, have undeniably produced good results due to both the local action of water that is rich in iron and copper, and the break from daily routine. It should be noted that in general, patients do see an improvement in their lichen planus symptoms while on holidays away from home.

Treatment approach

It is important for clinicians to always bear in mind the risk of transformation to cancer that affects around 1% of patients, meaning that thorough monitoring is required. Treatment is prescribed in successive stages, beginning with topical corticosteroids.

Unfortunately, there is no effective treatment for lesions at the atrophic stage, and this is why it is essential to routinely offer long-term treatment for the inflammatory and ulcerative lesions that lead to atrophy, which can itself encourage malignant transformation.

Because treatments have only relative efficacy and limited effects over time, in that they do not prevent relapses, very strict monitoring is required for oral lichen planus. This should consist of appointments every 3 - 6 months depending on the stage of the initial lesions and how severe they are. Ulcerative, atrophic, and verrucous lesions must be given particularly close attention.

Improving hygiene

As with any lesion of the oral mucous membranes, the following recommendations are made: stop or significantly reduce use of tobacco, betel, coffee, alcohol, and foods that are damaging to the mucous membrane (spicy foods); practice good oral hygiene (use a soft toothbrush, attend to any oral problems, eliminate anything causing damage to the gums, and remove tartar often); have metal crowns replaced by porcelain ones, and follow a healthy lifestyle, trying to reduce stress.

LUPUS ERYTHEMATOSUS

It has been reported that in 50% of cases of systemic lupus erythematosus, oral lesions are present, and particularly affect the mid part of the cheek, lower lip, or the palate. These are fine, lacy white patches with short, radiating bands that sometimes outline a red, atrophic plaque. White lesions in lupus must be differentiated from lichen planus. It is not currently known whether there is any risk of transformation to cancer.

Treatment

Lesions often do not cause symptoms, in which case it is entirely justified not to treat them. The synthetic antimalarial drugs (hydroxychloroquine, 400 mg/day) that are effective on the lupus skin lesions are thought to be slightly less so on lesions of the oral mucous membranes. If the oral lesions cause discomfort (ulceration), a short course of topical corticosteroids (Buccobet®) may be prescribed.

GEOGRAPHIC TONGUE

(See chapter)

WHITE LESIONS CAUSED BY INFECTIONS

CHRONIC CANDIDIASIS

Chronic oral candidiasis can be the cause of white verrucous lesions that are generally found behind the commissure of the lips. These lesions may be associated with others such as bilateral angular stomatitis, or median rhomboid glossitis together with a lesion on the palate, opposite the tongue lesion. The presence of hereditary factors (any endocrine disease) or underlying immune deficiency should be investigated.

Treatment

If the usual topical or oral antifungal treatments fail, the next option is surgical removal of verrucous lesions and carrying out full histology checks on the biopsy specimen because a risk of transformation into cancer has been reported.

ORAL HAIRY LEUKOPLAKIA

These asymptomatic, ill-defined, irregular, white, vertical bands are found on the side edges of the tongue. They are an oral form of EBV infection within HIV infection. If they do not interfere with function there is no need for treatment.

HEREDITARY AND CONGENITAL DYSKERATOSES

WHITE SPONGE NAEVUS

This is a hamartoma with an autosomal dominant pattern of inheritance that appears in childhood.

It is characterised by spongy leukoplakia plaques with an irregular surface that are mainly found on the cheeks, and occasionally on the palate, tongue, and floor of the mouth.

These lesions persist indefinitely in adults, but there is no risk of progression to cancer; they do not require treatment.

HEREDITARY BENIGN INTRAEPITHELIAL DYSKERATOSIS

This inherited disease is characterised by hyperemic epibulbar conjunctiva that can lead to blindness, and leukoplakia plaques on the mucous membranes of the mouth. There is no risk of transformation to cancer.

DYSKERATOSIS CONGENITA

Dyskeratosis congenita or Zinsser-Engman-Cole syndrome is a very rare disease that is connected to disrupted telomerase activity, which is usually linked to the X chromosome, affecting boys. In the mouth, it is characterised by leukoplakia lesions that develop between the ages of 5 and 14. It is not uncommon for these oral lesions to develop into cancer and this is a worry after 10 - 15 years of disease progression, which is why periodic examinations are required to detect the signs of transformation. There is no treatment reported to be effective apart from long-term retinoid treatment, which is very unsafe at effective doses. Another feature of this condition is the development of blood disorders, principally bone marrow aplasia, between the ages of 10 and 20.

CONCLUSION

White lesions of the oral cavity are clinical lesions that can point to a number of causes, the main one being chronic tobacco toxicity. Histology findings in oral leukoplakia lesions indicate processes of varying seriousness, ranging from simple benign epithelial hyperplasia to a squamous cell carcinoma that is already invasive, passing through all the degrees of intraepithelial neoplasia in between. Histologic examination is therefore essential before management is addressed.

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