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Leukoplakia  

The term leukoplakia was first used in 1877 by Schwimmer to denote any white lesion of the oral cavity. This is the most common precancerous lesion of the oral mucosa. The use of different terminologies and definitions have made it difficult to properly evaluate the reported data on epidemiology, treatment results and rates of malignant transformation of oral leukoplakia. In order to promote uniform reporting, a new set of guidelines and clinical staging procedure were proposed in 1994 . Oral leukoplakia is now defined as “a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion”. In addition, a recommendation has been made to distinguish between a provisional clinical diagnosis and a definitive one. A provisional clinical diagnosis of oral leukoplakia is made when a lesion at the initial clinical examination cannot be clearly diagnosed as any other definable lesion of the oral mucosa with a white appearance. In such situations a definitive diagnosis is made by possible identification and elimination of suspected causative factors like chemical burn, frictional keratosis, habitual cheek or lip biting, papilloma, lupus erythematosus, white sponge nevus, candidiasis, lichen planus including lichenoid lesions, etc. Two to four weeks is a reasonable interval to observe the possible regression or disappearance of the white lesion after elimination of possible causative factors before subjecting the person to a biopsy. However, the histopathological features of several white lesions seen in the oral mucosa are not always characterisic. There is general agreement that leukoplakia now be used as a clinical term, without any histological connotation, to characterize predominently white intraoral lesions that cannot be rubbed off or diagnosed as another specific disease entity .

Leukoplakias are asymptomatic and are usually noticed by healthcare providers during routine examinations. It is diagnosed both by its clinical appearance and by the exclusion of other lesions that present as oral white lesions. A biopsy examination helps to explore other specific conditions that need exclusion before a white patch is confirmed as a leukoplakia. Microscopic evidence of dysplasia is not a prerequite for the diagnosis of leukoplakia. On the other hand, if a histological diagnosis of malignancy or carcinoma in-situ is made in a biopsy specimen from leukoplakia, the clinical diagnosis of leukoplakia is no longer valid, and the histological diagnosis of malignancy becomes the final diagnosis.

Aetiology:

All forms of tobacco use are major risk factors for oral leukoplakia (). The association is strong, consistent, reproducible, biologically plausible and shows a strong dose-response relationship. A high frequency of leukoplakia is observed in populations with a high prevalence of tobacco habits, particularly chewing, such as those in South and Southeast Asia . It is more frequently observed in men, due to their higher prevalence of tobacco habits. The risk of developing malignancies at lesion sites is greater in those with leukoplakia than in subjects without leukoplakia. A significant rate of regression of leukoplakia has been reported after stopping tobacco habits .

An association between candida infection and leukoplakia, especially non-homogenous leukoplakia, has also been shown, and higher rates of malignant transformation have been reported in candida superimposed leukoplakias . Some of the non-homogenous leukoplakic lesions revert to homogenous leukoplakia or even regress after treatment for candidiasis . However, it is controversial whether candida infection is one of the causes of leukoplakia or whether it is a superimposed infection in a preexisting lesion.

Implication of human papillomavirus (HPV) in the aetiology and potential for malignant transformation of oral pre-malignant lesion have been studied by several authors . However, the results vary and to a certain extent are inconsistent. A meta-analysis reported that the likelihood of detecting HPV was 2–3 times higher in precancerous lesions and 4–5 times higher in oral cancers than in normal oral epithelium . It has been reported that the prevalence of high-risk HPV types was significantly higher in oral squamous cell carcinomas, while low-risk types were often seen in oral precancers.

Several authors have reported chewing of areca nut without tobacco as a risk factor for oral leukoplakia . Similarly, some studies have reported alcohol as an independent risk factor for oral leukoplakia . However, others did not find any association between alcohol intake and oral leukoplakia . Alcohol has been reportedly associated with malignant transformation of oral leukoplakia . An inverse association of body mass index (BMI) with oral leukoplakia was observed in a case–control study from India .The highest quartile of BMI had a protective effect on oral leukoplakia compared to the lowest quartile. Dietary fibre, beta carotene, and intake of vegetables and fruits have been reported to be protective for oral leukoplakia . Leukoplakia has also been reported without any particular risk factor (idiopathic leukoplakia).

Subtypes of leukoplakia:

Clinically, leukoplakia is classified into homogeneous and non-homogeneous lesions. Homogeneous leukoplakia is defined as a predominantly white lesion of uniform flat, thin appearance that may exhibit shallow cracks and has a smooth, wrinkled or corrugated surface with a consistent texture throughout . Non-homogeneous leukoplakia is defined as a predominantly white or white-and-red lesion that may be irregularly flat, nodular or verrucous. Even though non-homogeneous leukoplakia has been further subclassified into ulcerated, nodular (speckled leukoplakia) and verrucous leukoplakia, this binary classification of homogeneous and non-homogeneous will reduce the confusion and misclassification associated with the use of multiple terminology, and will help to better understand the natural history of these lesions.

Proliferative verrucous leukoplakia is a rare clinical form of oral precancer, otherwise known as florid papillomatosis, characterised by multiple squamous papillary nodules. This is an aggressive form of oral leukoplakia, and nearly all cases of proliferative verrucous leukoplakia eventually undergo malignant transformation at multiple sites .

Natural history:

Leukoplakia may occur as a single localized lesion, multiple lesions, or as diffusely outspread lesions. In a systematic review, the pooled estimate of prevalence of leukoplakia was 2.6% globally; this study did not find any difference between geographical areas or between younger and older adults . However, leukoplakia occurs more among males than females. It is not clear whether homogeneous and non-homogeneous leukoplakias represent independent disease entities or a continuum of progressive clinical phases of the underlying disease process . In a cohort study from India, it has been reported that non-homogeneous lesions were preceded by homogeneous lesions . It is well known that oral leukoplakias undergo regression, but there is only limited information on the rate and factors influencing regression . Follow-up studies have clearly established that oral leukoplakia is a precancerous lesion for cancers of the oral cavity. It is reported that 3–17.5% of lesions may demonstrate malignant transformation over follow-up ranging up to 15 years (Table 1).

Table 1: Selected Studies on Malignant Transformation of Oral Leukoplakia.

Study/Year	Country	Number of cases	Observation (years)	% Malignant transformation
Pindborg et al. , 1968	Denmark	248	1-10	4.4
Silverman and Rosen, 1968	USA	117	1-11	6.0
Mehta et al. , 1972	India	117	10	0.9
Silverman et al. , 1976	India	4762	2	0.13
Bánóczy, 1977	Hungary	670	1-30	6.0
Silverman et al. , 1984	USA	257	7.2 Mean	17.5
Lind, 1987	Norway	157	6-16	8.9
Schepman et al. , 1998	Netherlands	166	2.5 Median	2.9 annual
Shiu et al. , 2000	Taiwan	435	1-10	26
Saito et al. , 2001	Japan	142	4 Mean	6.3
Holmstrup et al. , 2006	Denmark	254	7.5 Mean 6.6 Mean	12 (surgical series) 4 (non- surgical series)

The frequency of malignant transformation is lower in cohort studies compared to hospital based studies and the rate of malignant transformation increases over time. Clinical type and size of the lesion are the important predictors of malignant transformation, and other factors like gender and site have no influence . A higher risk of malignant transformation is observed in non-homogeneous leukoplakia compared to homogeneous leukoplakia .The malignant potential is almost 7 times higher for non-homogeneous leukoplakia compared to homogeneous type . Even though a higher malignant transformation has been reported for lesions in the ventral and lateral margins of the tongue and the floor of the mouth , others did not find any site predilection for malignant transformation . Although epithelial dysplasia is an important predictive factor of malignant transformation, not all dysplatic lesions become malignant. On the other hand, non-dysplastic lesions may become malignant as well . All leukoplakias should be viewed with suspicion because even small, subtle lesions can manifest significant dysplasia or harbour unsuspected carcinoma .

Diagnosis:

We advise oral punch or incision biopsy as a routine procedure in the overall evaluation of oral leukoplakia, irrespective of the clinical appearance, to assess the presence of dysplasia and to rule out underlying malignancy. Lesions with candidiasis should be reevaluated after 3 weeks of continuous topical antifungal therapy and elimination of suspected local irritants. Conventional biopsy is recommended for all oral leukoplakia that persists after this period. A schematic diagram to assist recognition of oral leukoplakia by eliminating other mucosal disorders was drawn up by experts at the workshop coordinated by the WHO Collaborating Centre for Oral Cancer and Precancer in the UK (figure 1) .

Surface nodularity of lesions, appearance of white or red masses with surface pebbling or ulceration, especially at the margins of the lesions, increased firmness and induration, unexplained haemorrhage and chronic ulcer formation in a preexisting leukoplakia, should herald the suspicion of malignant transformation and warrants prompt biopsy and further management. Small, early oral cancers developing in preexisting leukoplakic areas can be easily removed with minimal surgical deformity and with good treatment outcome.

Histopathology:

The histological findings in oral leukoplakias are highly variable, ranging from hyperkeratosis and hyperplasia to atrophy and varying grades of dysplasia. Oral mucosa responds to chronic injury or carcinogenic stimuli by either hyperplasia or atrophy. The white thickening of the normally thin, pink mucosa is due to the increase of epithelial keratinocyte compartment or prickle cell layer (acanthosis) and/or hyper orthokeratosis (accumulation of surface keratin) and parakeratosis (persistence of nuclei or nuclear remnants in the keratin layer). The granular cell layer is often thick and extremely prominent in cases of hyperorthokeratosis, but is seldom observed in even severe cases of hyperparakeratosis. In most instances, basilar cells and keratinocytes in the lower portions of the epithelium show no evidence of dysplasia, except a mild basilar hyperplasia. But 10–25% of cases may show histological features of various grades of dysplasia . Dysplasia refers to abnormal epithelial growth characterised by cytologic, maturational and architectural changes. The criteria used for diagnosis of dysplasia is given in table 2 .

Non-homogeneous leukoplakias are more likely to harbour dysplasia as compared to homogeneous leukoplakia. More than 90% of the homogeneous leukoplakia has low rates of epithelial dysplasia and malignant transformation over prolonged observation time. Mixed white and red lesions histologically show regions of epithelial hyperplasia, hyperkeratosis, epithelial atrophy and submucosal inflammation. They often exhibit epithelial dysplasia.

In many instances mild dysplasia may represent reversible reactive changes rather than a neoplastic transformation. The term atypia rather than dysplasia may be used by some pathologists to convey the histological uncertainity in mild dysplasia. In mild dysplasia the cytological atypia is minimum, and the architectural disturbances are noted in the lower third of the epithelium. In moderate dysplasia the degree of cellular atypia is greater, and the architectural disturbances extend into the middle third of the epithelium. The changes in moderate dysplaia are more appreciable. In severe dysplasia marked cellular atypia is noted with architectural changes involving more than two thirds of the thickness of the epithelium.

The histologic assessment of oral epithelial dysplasia is notoriously unreliable, challenging and variable. A tissue specimen from a biopsy may not be representative of the whole lesion. Many studies show intra- and inter-observer variation in diagnosing dysplasia. Molecular studies may introduce more objectivity. Studies have shown that p53 protein over-expression and other molecular markers such as loss of heterozygosity and DNA ploidy are strong predictors of malignant transformation . To date no molecular marker or panel of markers has been identified to specifically predict the malignant potential of leukoplakia. However, the newer molecular markers could be considered complementary to conventional clinical prognostic evaluation.

Differential diagnosis:

The following differential diagnosis should be kept in mind whenever a clinical diagnosis of leukoplakia is made:

• Surface debris. This can be scrapped off with a tongue blade or gauze
• Acute pseudomembranous candidiasis (Thrush). White, curd-like or cottony patches or plaques, most frequently occurring on the buccal mucosa and tongue, but also seen on the palate, floor of mouth and gingiva. They are usually associated with a burning sensation, and the white plaque can usually be wiped away with gauze, leaving a tender, red area beneath, which may bleed
• Fordyce granules
• Reactive hyperkeratosis. A benign epithelial response, usually due to trauma from a fractured tooth or dental restoration
• Leukoedema
• Lichen planus
• Linea alba buccalis
• Submucous fibrosis

In selected situations, these conditions, particularly oral submucous fibrosis, may coexist with oral leukoplakia.

Management:

The various approaches for the management of leukoplakia include medical and surgical options:
Medical management

• Cessation of tobacco and alcohol use
• Topical application of retinoids
• Systemic treatment with Vitamin A, beta-carotene, lycopene, isotretinoin, etc.

Surgical management

• Conventional surgical excision
• Laser excision
• Photodynamic therapy
• Cryotherapy
• Electrocautery

Unlike management of cervical precancers, treatment of oral precancers is often challenging, and the results are often not satisfactory. The main objective of treating leukoplakia is to prevent malignant transformation. Although several management regimes have been suggested, results in term of preventing malignant transformation are highly variable, particularly due to the field cancerisation effect . Treatment may be effective in the resolution of lesions; however, relapses and adverse affects are common . Stopping the use of tobacco and alcohol and management of superadded fungal infection may result in the regression of lesions. A diet rich in fruits and vegetables may help in preventing neoplastic transformation in conjunction with tobacco/alcohol cessation. Possible courses of action, following a clinical diagnosis of leukoplakia include a policy of close follow-up at 3–6 monthly intervals with biopsies as and when required, in conjunction with tobacco/alcohol control and a diet rich in vegetables and fruits.

Conservative surgical excision remains the treatment of choice for small leukoplakias . However, recurrences and malignant transformation can still occur in the treated area. A recurrence rate of 10–20% and cancer development in 3–12% in previously excised areas have been documented . Electrocautery, cryosurgery, laser ablation and photodynamic therapy are other alternative methods of treatment .

Several non-surgical methods have also been tried in the management of oral leukoplakia. Treatment with topical retinoids, anti-inflammatory drugs and bleomycin are of dubious value . Systemic retinoids may be effective in the resolution of lesions; however, relapses and adverse effects are common . Vitamin A and beta carotene have been found to be effective in the regression of leukoplakias, but relapses are common following cessation of medication . Studies investigating the use of high-dose induction systemic isotretinoin (1.5 mg per kilogram of body weight per day) followed by a low dose of isotretinoin (0.5 mg per kilogram per day) report stabilization of the majority of lesions and a more effective response than beta-carotene in preventing malignant changes .

Long-term follow-up, even after removal, is essential because recurrences are frequent and additional leukoplakias may occur. Clinical evaluation at 6–12 month intervals is recommended . Treatment sites that remain disease-free for three years may no longer be followed-up, but any person with residual leukoplakia should be followed-up, possibly for a lifetime.

Image	Caption
	Figure 1: Schematic representation of the steps in diagnosis of oral leukoplakia adapted from Warnakulasuriya et al .
	Table 2: Criteria used for diagnosing dysplasia extracted from Blue Book (Head and Neck tumours (p177) ).
	Figure 2: Leukoplakia with mild dysplasia. Hyper keratotic, with hyperplastic epithelium with elongated rete pegs and abnormal cells in the lower one-third of the epithelium.
	Figure 3: Leukoplakia with moderate dysplasia. Hyper keratotic, with hyperplastic squamous epithelium with abnormal cells in two-thirds the thickness of epithelium.
	Figure 4: Leukoplakia with severe dysplasia. Hyperplastic, with hyperplastic squamous epithelium with markedly abnormal cells in more than two-thirds of the epithelium.