https://doi.org/10.5272/jimab.2017231.

1495
Journal of IMAB
Journal of IMAB - Annual Proceeding (Scientific Papers). 2017 Jan-Mar;23(1):
ISSN: 1312-773X
https://www.journal-imab-bg.org
MANAGEMENT OF ORAL LEUKOPLAKIA -
ANALYSIS OF THE LITERATURE
Elitsa G. Deliverska, Milena Petkova.
Department of Oral and Maxillofacial surgery, Faculty of Dental Medicine,
Medical University – Sofia, Bulgaria

ABSTRACT MATERIAL AND METHODS

Oral leukoplakia is the most common potentially An electronic search (MEDLINE, EMBASE, and con-
malignant disorder affecting oral cavity. Various surgical trolled clinical trials (CCT) were reviewed. 18 articles were
and non-surgical treatments have been reported, but cur- chosen and analyzed about management of different types
rently there is no universal consensus on the most appro- of oral leukoplakia.
priate one and on the duration or interval of follow-up of
patients with this condition. RESULTS AND DISCUSSION
The aim of this article is to present a review of the Epidemiology
management of oral leukoplakia according to the literature The prevalence of oral leukoplakia, worldwide, is
until now. approximately 1%-2% for all ages together. There are geo-
Management of oral leukoplakia should begin with graphical differences with regard to gender distribution.
elimination of risk factors (if any) such as tobacco abuse, Leukoplakias are usually diagnosed after the fourth dec-
betel chewing, alcohol abuse, superimposed candida infec- ade of life and are six times more common among smokers
tion over the lesion etc. than among non-smokers. Alcohol may be an independent
Conservative treatment includes use of or synergistic risk factor. There may be a potentially im-
chemopreventive agents such as vitamins (vitamins A, C, portant and causal association between human
E), fenretinide (Vitamin A analogue), carotenoids (beta- papillomavirus and oral potentially malignant disorders.
carotene, lycopene), bleomycin, protease inhibitor, anti-in- Erythroplakia is much less common than
flammatory drugs, green tea, curcuma etc. leukoplakia. No reliable prevalence figures are available;
Surgical treatment includes conventional surgery, estimated figures vary from 0.02% to 0.83%.The etiology
electrocoagulation, cryosurgery, and laser surgery (excision is unknown, but tobacco and alcohol are probably predis-
or evaporation). posing factors.
The main purpose of oral leukoplakia management
is to avoid malignant transformation of the lesion or if this Etiology
happened to detect this in early stages. Etiology of OL is not clearly established yet. [4] It is
considered multifactorial origin of the lesion. [5] Smoking,
Keywords: Leukoplakia, management, surgical, non- alcohol abuse, lasting mechanical injuries, Candida albi-
surgical treatment, cans infection and differences of local trauma or galvanic
potentials are reported as the most important causative fac-
INTRODUCTION tors. Oral leukoplakia can accompany systemic disorders
Oral leukoplakia (OL) is the most frequent precan- like hormonal disturbances, gastroaesofagal reflux, dimin-
cerous lesion of the oral cavity. [1, 2] Oral leukoplakia is ished saliva secretion or iron deficiency anemia. It is also
defined by WHO (1997) as “a predominantly white lesion stated that EBV, HPV (16 and 18 types), HSV and HIV vi-
of the oral mucosa that cannot be characterised as any other ruses significantly influence OL development and carcino-
definable lesion”. [2, 3, 4] genic transformation of this lesion. [4]
In 2012 van der Waal [5] proposed a new definition
which seems more oportune as it includes the histological Classification/clinical aspects
confirmation: “A predominantly white lesion or plaque of Considering the macroscopic appearance, oral
questionable behavior having excluded, clinically and his- leukoplakia is broadly classified into homogeneous and
topathologically, any other definable white disease or dis- non-homogeneous subtypes.[2, 3]
order”. This one hasn’t been assessed yet by WHO but it The distinction between this two types is purely
has good chances for acceptance by the physicians. clinical, based on surface colour and morphological (thick-
ness) characteristics, and do have some bearing on the out-
Purpose come or prognosis. [6]
The aim of this article is to present a review of the
management of oral leukoplakia according to the contem- Homogeneous plaques are predominantly white, of
porary standards. uniform flat, thin appearance with shallow cracks of sur-

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face keratin, and have a smooth, wrinkled, or corrugated and non-dysplastic lesions just 9.5%. [2]
surface with a consistent texture throughout. [2, 3] Despite It must be noted that oral epithelial dysplasia has
the fact that the risk of malignant transformation is rela- no specific clinical appearance.[6] It can be present in any
tively low - about 5% [6], these lesions seem to warrant apparently benign clinical white lesion. [2]
careful follow-up as well. [7] Despite advances in molecular biology, nowadays
there are no reliable markers to predict the malignant trans-
Non-homogeneous plaques varieties include [6]: formation of oral leukoplakia. It has been reported that a
• speckled: mixed, white and red few markers such as Ki-67 (Mib-1) and bromodeoxyuridine,
(erythroleukoplakia), but retaining predominantly white and the combined biomarker score of chromosomal polys-
character; omy, p53, and loss of heterozygosity might be strong pre-
• nodular: small polypoid outgrowths, rounded red dictors for malignant transformation, but this is not gener-
or white excrescences; ally adopted in clinical practice.[2, 3]
• verrucous: wrinkled or corrugated surface appear- The risk factors for malignant transformation include
ance. age, site, size, appearance, presence of dysplasia, and ab-
• proliferative verrucous leukoplakia (PVL). Prolif- normal DNA content, but there is no single predictive fac-
erative verrucous oral leukoplakia is a subtype of verru- tor or any reliable biomarker predictive of malignant trans-
cous leukoplakia according to some authors[3,6]. It in- formation. [3]
volves multiple mucosal areas with confuent, exophytic Main factors associated with increased risk of ma-
and proliferative features. [2] The PVL is characterised by lignant transformation are patients who do not smoke and
an aggressive evolution, resistance to treatment, and high are over 60 years of age; lesions that are non-homogene-
rate of malignant transformation. [3, 5] ous or are wide spread; lesions located in high-risk areas
Non-homogeneous lesions carry a higher risk of ma- and those larger than 200mm2 ; and histopathologically
lignant transformation. [6] confirmed epithelial dysplasia. [3]
Additional clinical descriptions that may assist the High-risk areas for malignant transformation have
characterization of oral leukoplakia are [6]: been identified as floor of the mouth, lateral borders of the
· Etiological description: clearly associated with to- tongue, soft palate and retromolar areas. [8]
bacco or areca nut use; idiopathic. According to some authors high malignant inciden-
· Site description giving anatomical sub-site in the ces for patients with high-grade dysplasia occurred during
mouth or oropharynx. the first 2–3 years of follow-up. [8]
· Size or extent of the lesion(s). The patients with histologically confirmed leukoplakia
Leukoplakia is a clinical term and the lesion has no are reported to have no malignant transformation in 86.6%
specific histology. [6] Pathohystological examination of after 3 years of follow-up and 82.0% after 5 years. [2]
leukoplakia can show hyperkeratosis, atrophy, acanthosis Although clinical appearance such as non-homoge-
and may or may not demonstrate different degrees of epi- neous oral leukoplakia and anatomical site (notably the
thelial dysplasia. [2, 6] Dysplasia reflects histological floor of the mouth and the ventral tongue) can help to iden-
changes which are followed by the loss of uniformity of tify lesions with a high risk of malignant transformation,
the architecture of the epithelial cells.[5] there are no reliable ways to predict the behavior of indi-
vidual lesions or to guide clinical management without bi-
According to these findings, oral leukoplakia can be opsy examination. [3]
distinguished as dysplastic and non dysplastic lesions. Patients with multiple oral precancerous lesions and
Based on histological examination the presence of dyspla- extensive areas of mucosa that may show signs of dys-
sia has been associated with a risk of malignant transfor- plastic change are particularly difficult to manage. Modern
mation to oral cancer. [3] concepts of carcinogenesis have emphasised the existence
At the last world seminar of Oral Medicine about of molecularly altered preneoplastic fields (field of canceri-
potentially malignant lesions, London 2010, it has been rec- zation) from which multiple lesions can develop. Wide-
ommended a binary classification of histological changes. spread lesions have been shown to have higher rates of
[5] Lesions are graded as low risk (mild and moderate dys- malignant transformation than those that are more
plasia) and high risk (severe dysplasia and carcinoma in localized. [3]
situ) depending on the architecture and cytological
changes. [3] This aims to reduce subjectivity in grading DIAGNOSIS
dysplasia, thus increasing the possibility of conformity be- Histopathology examination is at present still the
tween histological interpretations of different pathologists. gold standard for diagnostic purposes. DNA ploidy meas-
[5] urements may be helpful in identifying lesions that carry a
Epithelial dysplasia has been regarded as one of the high risk of malignant transformation.
most important indicators of future malignant potential. [3] The biopsy should be taken at the most clinically
Dysplastic oral leukoplakia has a 5 times higher risk of ma- suspicious area, if any, such as redness, an area of surface
lignant transformation than non-dysplastic. [2, 3] A study thickening or a symptomatic area. In patients with multifocal
showed that for a period of 5 years follow-up dysplastic or widespread leukoplakia multiple biopsies (‘field map-
lesions had a incidence of malignant transformation of 41% ping’) should be considered. Particularly in the case of a

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non- homogeneous leukoplakia an incisional biopsy may not been reported, but currently there is no consensus on which
be representative. In small leukoplakias, e.g. < 2 - 3 cm, an is best. [3] The main aim of oral leukoplakia management
excisional biopsy may be considered. The value of oral brush is to avoid malignant transformation. [2]
cytology is a subject of controversy, as is the use of toluidine Proper clinical examination should be done on the
blue. [7, 8] day of reporting of the lesion; type, size and location of
Malignancies may develop at the site of treated or lesion should be carefully recorded. [9]
untreated leukoplakia, but may also occur elsewhere in the A consideration of their risk potential i.e. low risk
oral cavity or upper aerodigestive tract. The commonly rec- leukoplakia and high risk leukoplakia should be done. [9,
ognized factors that statistically carry an increased risk of 10]
malignant transformation into a squamous cell carcinoma Low risk leukoplakia: Leukoplakia lesions having
are listed below. Of these risk factors, the presence of epithe- no dysplastic features or having mild dysplasia associated
lial dysplasia – often correlating with a clinically non- ho- with following features is considered as low risk
mogeneous, erythroleukoplakic subtype – is in general re- leukoplakias.
garded the most important indicator of malignant potential. a. Site not in high risk area
Nevertheless, it should be recognized that some dysplastic b. Size less than 200 mm
lesions may remain unchanged or may even show complete c. Homogenous clinical form
regression.
Furthermore, carcinomatous transformation may also High risk leukoplakia: A leukoplakia is considered
take place in non-dysplastic leukoplakia. to be at a high risk if it shows dysplasia associated with
In several studies from the Western world, the bor- following features:
ders of the tongue and the floor of the mouth have been a. Site in high risk area
mentioned as high-risk sites, while in a study from Denmark b. Size greater than 200mm
also size was shown to be of importance, particularly when c. Non homogenous clinical form [9, 10]
exceeding 200 mm2..
In spite of tremendous progress in the field of mo- Differential diagnosis
lecular biology, there is as yet no single marker or set of White lesions of oral mucosa often present problems
markers that reliably enables to predict malignant transfor- of differential diagnosis, which are of primary importance
mation of leukoplakia in an individual patient with when assessing precancerous changes in the mouth. The
leukoplakia, perhaps with the exception of DNA ploidy precancerous character of oral leukoplakia is well estab-
measurements. The use of non-invasive genetic tests, using lished, and the “high-risk” type: erosive-dysplastic
exfoliated or brushed cells of lesional tissue or molecular leukoplakia of greater malignant potential has been thor-
markers from saliva may prove to be a step forward in the oughly investigated. Because of their possible association
search for relevant prognostic markers . Most erythroplakias with oral carcinoma, some clinical types of oral lichen pla-
will probably undergo malignant transformation. There are nus, namely, the atrophic-erosive forms indicate caution in
not enough documented series that would allow to calcu- their treatment and supervision. Epithelial dysplasia is of-
late a reliable annual malignant transformation rate. ten associated with candidiasis and discoid lupus ery-
Reported risk factors of statistical significance for thematosus, but neither this, nor such other white lesions
malignant transformation of leukoplakia, listed in an at ran- as white sponge naevus or morsicatio buccarum, are con-
dom order (not reliable for use in the individual patient) sidered to be preneoplastic. All these white lesions may be
· Female gender clearly identified, differentiated, and circumscribed as clin-
· Long duration of leukoplakia icopathological disease-entities, by clinical, histopatho-
· Leukoplakia in non-smokers(idiopathic leukoplakia) logical and ultrastructural methods, thus facilitating early
· Location on the tongue and/or floor of the mouth diagnosis, treatment and prevention of possible malignancy.
· Size >200 mm2 • Leukoedema
· Non-homogeneous type • Lichen planus
· Presence o C. albicans • Chemical burn
· Presence of epithelial dysplasia • Morsicatio buccarum (habitual cheek biting)
· DNA aneuploidy • Candidosis
· History of previous head-and-neck carcinoma • Psoriasis
Even though numerous manuscripts have dealt with • Lupus erythematosus
management of oral leukoplakia, still there is lack of a • White sponge nevus
proper protocol and no universal consensus on its manage-
ment. [9] The standard treatments for OL range from care- Management
ful consideration to complete excision in histological clear Clinical examination is repeated after 2-3 weeks to
margins. [4] assess the regression in size of lesion in low risk as well as
Even despite treatment the disease can recur, undergo high risk leukoplakia. After 2-3 weeks of habit cessation,
malignant transformation, or new lesions can develop in if there is regression in size of leukoplakia than follow up
patients treated previously. [3] is done initially every three months followed by every 6-12
Various non-surgical and surgical treatments have months. [9]

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 Low risk lesion which is not regressing in size even cific natural or synthetic chemical agents to reverse, sup-
after habit cessation or in cases of high risk lesion, biopsy press, or prevent carcinogenesis before the development of
is mandatory [9] in order to assess the degree of epithelial invasive malignancy [9], thus reducing the morbidity and
dysplasia. [4] mortality associated with it. [11]
In cases which show no signs of dysplasia, then con- The use of photodynamic therapy has been also re-
servative treatment is advised. In cases of mild, moderate ported. [3]
or severe dysplasia, both conservative and surgical treat- Careful and routine follow-up observations of
ment is advised. [9] leukoplakia are appropriate in conjunction with elimina-
Oral leukoplakia presenting low to moderate malig- tion of any risk-associated behavior or habits. [10] In case
nant risk may be either completely removed or not, and the of no improvement, treatment should become more inva-
decision should consider other factors such as location, size sive. [1]
and, in the case of smokers, the patient’s engagement in
smoking cessation. [4, 10] Surgical treatment still remains one of the most
In the presence of moderate or severe epithelial dys- common treatment methods in OL and should be the
plasia, surgical treatment is recommended. [4] method of choice in OL with histologically diagnosed epi-
Non-surgical treatment can be considered as a good thelial dysplasia. [1]
choice in homogenic OL without dysplasia or as an initial Surgical treatment includes conventional surgery,
treatment in other cases of OL. [1] electrocoagulation, cryosurgery, and laser surgery (excision
Non-surgical treatments cause minimal adverse ef- or evaporation). [3]
fects, particularly in patients with widespread oral Surgical treatment for OL may prevent the develop-
leukoplakia that involves a large area of the oral mucosa, ment of oral squamous cell carcinoma, provided by assur-
or in those with medical problems who have high surgical ing that the resection margins are adequately thick and free
risks, or when patients refuse surgical intervention. [3, 4, of epithelial abnormalities. However, it has been shown that
10] surgical intervention does not appear to prevent OL from
Additionally, potential advantages of the nonsurgi- developing recurrence. Malignant transformation of these
cal treatment of OL include easy application that does not lesions is independent of drug or laser therapy. [4]
require treatment at a medical center and relative low cost.
[10] Non-surgical treatment of oral leukoplakia
1. Carotenoids
Treatment options Carotenoids belong to a group of highly hydropho-
Any treatment of oral leukoplakia should begin with bic molecules with little or no solubility in water. [4, 10]
elimination of risk factors such as tobacco abuse, betel 1.1. Beta-Carotene
chewing, alcohol abuse, superimposed candida infection Beta-carotene is a vitamin A precursor.[2, 4] This
over the lesion etc. carotenoid is commonly found in dark green, orange or yel-
The ceasing of tobacco use is a prior action in case lowish vegetables, such as spinach, carrots, sweet potato,
of tobacco associated leukoplakia. [2] mango, papaya, and oranges. [10]
Up to 60% of leukoplakias regress or totally disap- The use of beta-carotene has been recommended for
pear if tobacco use is stopped. Leukoplakias induced by the prevention of potential malignant lesions, such as OL
smokeless tobacco may resolve if the habit is stopped. [10] and cancer, possibly oral cancer. The potential benefits and
Counseling delivered by physicians and other pro- protective effects against cancer are possibly related to its
fessionals significantly increases tobacco quit rates. Even antioxidant action. [4]
a brief (3-minute) period of counseling to urge smoker to This function is accomplished through a ligation be-
quit results in smoking cessation rates of 5-10%. [9] tween beta-carotene and oxygen, which is an unstable re-
Some candidal leukoplakias respond, at least par- active molecule, thus diminishing the damaging effects of
tially to antifungal drugs (smoking should also be stopped) free radicals. [10]
and dysplasia may regress. In view of the evidence linking It has been shown that beta-carotene has a better
alcohol and tobacco, betel, and diet, to the development therapeutic clinical response in preventing oral
of potentially malignant and malignant oral epithelial le- leukoplakia lesions in smokers than in nonsmokers.
sions, it would seem reasonable therefore, that habits such A known side effect of excessive beta-carotene con-
as the use of tobacco and alcohol should be actively dis- sumption is a change in skin color, which becomes very
couraged, and a good diet and oral hygiene encouraged. yellowish, called carotenoderma, which disappears in a few
[10] weeks after the reduction of consumption. [4]
Some studies report that clinical resolution of oral
Conservative treatment includes use of chemopre- leukoplakia ranges from 4% to 54%, with dosages regimes
ventive agents such as vitamins (vitamins A, C, E), from 20 to 90mg/day of beta-carotene in time periods from
fenretinide (Vitamin A analogue), carotenoids (beta-carotene, 3 to 12 months. [2, 4]
lycopene), bleomycin, protease inhibitor, anti-inflammatory 1.2. Lycopene
drugs, green tea, curcuma etc. [3, 9] Lycopene is a fat-soluble red pigment found in some
Chemoprevention can be defined as the use of spe- fruit and vegetables. [2] The greatest known source of

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lycopene is tomatoes. [10] Several other processes are influenced by retinoids,
There is a positive relationship between lycopene such as the expression of growth factors and kinases, on-
consumption and a reduction in the risk of the develop- cogenesis, apoptosis, production of collagen matrix, im-
ment of degenerative diseases caused by free radicals, such mune and inflammatory responses, cell differentiation, em-
as cancer and cardio-vascular diseases. [2] bryonic morphogenesis and carcinogenesis.[4, 10]
Lycopene appears to be a very promising antioxi- Supplementation with retinoids for oral leukoplakia
dant as a treatment modality in oral leukoplakia and can treatment begin in the 1960s, however, this treatment was
protect cells against damage.[4, 10] not widely accepted due to its side effects-hypervitamino-
In addition to its antioxidizing property, lycopene sis, teratogenic effects, toxicity, and alterations in various
also has the capacity to modify intercellular exchange junc- organic systems. [2, 4]
tions, and this is considered to play a protective role against Topic retinoid were initially tested against diseases
progression of dysplasia by inhibiting tumor cell prolifera- related to keratinization. [10]
tion. Lycopene brings about histological changes of a sig- Studies focusing on topical vitamin A and their
nificant degree in patients with oral leukoplakia. [4, 10] derivates in the management of patients with OL have been
In vitro experiments have shown the inhibition of reviewed by Gorsky and Epstein. [10] They used 0.05%
the process of human neoplastic cellular growth by tretinoin gel that was applied topically 4 times per day for
lycopene, since this protein interferes in growth factor the management of non-malignant oral white lesions in 26
receptor signaling and, thus, in cellular cycle progression. patients (17 men and 9 women) with a mean age of 62
[10] Lycopene is hypothesized to suppress carcinogen-in- years. The vitamin A acid gel was applied locally for a
duced phosphorylation of regulatory proteins such as p53 mean of 3.5 years in patients who experienced clinical im-
and Rb anti oncogenes and stop cell division at the Go-G provement. Although a complete clinical remission was re-
1 cell cycle phase. [9] ported in 27% of patients, a partial response was noted in
Some authors tried to estimate the relation between 54% of patients, and clinical recurrence was experienced
nutrient intake and prevalence of oral leukoplakia. They in about 50% of patients after the topical treatment was
observed that tomato consumption, the main source of discontinued. Side effects of only a localized soreness were
lycopene, has the most protective effect on oral reported by only 19% of patients. [9]
leukoplakia among all dietary factors. [10] Lycopene is The topical use of 13-cis retinoic acid has been
better absorbed in oil resin capsules and in tomato juice shown to be effective in resolving oral leukoplakia. But
than in the form of raw tomatoes. [10] they are limited because recurrences appear after short pe-
A study evaluated lycopene in oral leukoplakia for riods of cessation of the treatment. In the systemic use with
a three months period, with dosages regimes from 4mg/day dosage of 300.000 IU of retinoic acid, a clinical resolution
and 8mg/day and patients had clinical resolution 25 and of the 50% has been demonstrated. [2, 10]
55%, respectively. [2] In a recent study the results obtained on using topi-
It has been reported that a daily dose of 8 mg of cal retinoid for the treatment of proliferative verrucous
lycopene was more effective than 4mg a day. [4] leukoplakia, involving variable concentration of tretinoin
No systemic significant toxic effects of lycopene or isotretinoin in gel form (0.05% to 0.1%), are generally
have been observed and there is no evidence of side ef- similar to those obtained with systemic retinoid.[2]
fects from the treatment with lycopene. Lycopene is a prom-
ising candidate in reducing cancer and chronic diseases in 2.2. Vitamin E
human beings. [10] Vitamin-E is the collective term for a family of chemi-
cal substances that are structurally related to alpha-toco-
2. Vitamins pherol. Alpha-tocopherol, the major constituent of Vitamin
2.1. Retinoids (Vitamin A/ Retinol) E has anti-tumor proliferation capacity as well as function
The current definition of retinoid includes all the as a free radical scavenger to prevent lipid peroxidation of
natural and synthetic compounds with an activity similar polyunsaturated fatty acids. [11]
to that of Vitamin A. [2, 10] It is found in plant oil, margarine, and green leaves.
The most biologically, naturally occurring retinoid [10]
is vitamin-A. Vitamin A, also known as retinol, is an alco- Benner et al., in his trial in 1993 showed that among
hol that can be converted into an aldehyde (retinal) or 43 patients with oral leukoplakia who took vitamin E twice
retinoic acid. [9] daily for 24 weeks had clinical response of 46% and histo-
Retinoids interact with surface receptors and pen- logical response of 21%. The treatment was well tolerated,
etrate the cell. They are subsequently metabolized and without any toxicity higher than grade 2 and with good
transported to the nucleus through several proteins.[4, 10] compliance. [11]
Vitamin A is required in the normal pathway of epi- On the other hand, Miller et al., performed a meta-
thelial cell differentiation and production of keratin. [9] An analysis of the dose-response relationship between vitamin
association between vitamin A deficiency and the en- E supplementation and total mortality by using data from
hanced susceptibility to carcinogenesis was reported with randomized controlled trials. It was found that high doses
an increased risk for developing different epithelial carci- of vitamin E supplementation (> 400 IU/d) may increase all-
nomas. [9] cause mortality and should be avoided. [11]

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 The recommended daily limit rates are 10 mg/day for 3. Anti-neoplastic agents:
adult men and 8 mg/day for adult women. [10] 3.1. Bleomycin
Bleomycin is a cytotoxic antibiotic which was first
2.3. L-Ascorbic Acid (L-AA)/ Vitamin C used for the treatment of neoplasms. It can be used as an
L-AA has antioxidizing properties and reacts with alternative for treatment of oral leukoplakia. [2, 10] It is
superoxide produced as a result of the cells’ normal meta- not very often used in practice for its adverse effects [2]
bolic processes; this inactivation of superoxide inhibits the The most commonly adverse effects are muco-cuta-
formation of nitrosamines during protein digestion and neous reactions, which include stomatitis, alopecia, pruritic
helps avoid damage to DNA and cellular proteins.[10] Vi- erythema, and vesiculation of the skin. [2, 10]
tamin C can be found in citrus fruits such as kiwi, straw- Topical bleomycin in treatment of OL was used in
berries, papaya, mango etc. dosages of 0.5%/day for 12 to 15 days or 1%/day for 14
The current US recommended daily allowance for days. [10]
ascorbic acid ranges between 100–120 mg/per day for Topical administration of bleomycin usually reduces
adults. It has been suggested that a daily intake of at least lesion size and has little toxic side effects. It is beneficial
140 mg/day is required for smokers because they usually to use bleomycin adjuvant with the surgical procedure for
present a reduction of the L-AA concentration in serum extensive leukoplakia to decrease the size of lesion before
leukocytes. [10] surgery. This helps to avoid grafting after removal of the
L-AA toxicity does not occur, since vitamin is wa- lesion and prevent the dysplastic change of benign form
ter-soluble. of lesion. [10]
The ability of L-AA to maintain oral mucosa integ- In a study, eight patients with OL were treated by
rity is very little documented. [10] the daily application of a 0.5% solution of bleomycin sul-
There are no studies regarding the efficacy of the use phate in dimethyl sulphoxide (DMSO). After 12 to 15 ap-
of L-AA alone for OL treatment. [10] plications, the white patch peeled off and the resultant raw
Some studies conducted a randomized controlled trial suface was epithelialized over the following 14 days. Re-
on treatment of oral leukoplakia with low dose of beta caro- peated biopsies showed a significant reduction of dyspla-
tene and vitamin C supplements. Vitamin C in the study was sia and keratinisation. The use of topical 1% bleomycin in
neither effective for clinical remission, nor for protection DMSO was evaluated for the treatment of dysplastic OL.
against the development of cancer. [10, 11] Bleomycin was applied once daily for 14 consecutive
days to lesions of the oral mucosa in 19 patients. It was
2.4. Fenretinide well tolerated with minor mucosal reactions. Immediate post
The compound N- (4-hydroxyphenyl) retinamide, treatment biopsies showed that 75% of patients had reso-
also known as fenretinide (4-HPR) was synthesized in the lution of dysplasia. Ninety-four percent of the patients at-
United States in 1960 and is used for treating OL. [4] tained at least partial clinical resolution. After a mean fol-
It has proven to be less toxic than many other vita- low-up period of 3.4 years, 31.6% of patients had no clini-
min A analogues. 4-HPR is well tolerated, and no local or cally visible lesions. In 2 patients (11%), malignant trans-
distant side effects are observed. [10] formation occurred. [10]
A characteristic feature of 4-HPR is its ability to in-
hibit cell growth through the induction of apoptosis with 4. Polyphenols as chemo-preventive agents
mechanisms that may be both receptor-dependent and 4.1. Curcumin
receptor-independent. [10] Curcumin has been used for thousands of years in
This compound is used for the chemo-preventive traditional Indian medicine. [12]
treatment of various diseases, and has been studied and Curcumin reportedly possesses several pharmaco-
tested in clinical trials for the treatment of OL. [4] logical properties, including anti-inflammatory, antimicro-
Eight patients with diffuse (non operable) oral lichen bial, antiviral, antifungal, antioxidant, chemo-sensitizing,
or OL were treated with 4-HPR applied topically twice radio-sensitizing, and wound healing activities. It is known
daily. After one month of therapy, two patients had com- to suppress tumor initiation, promotion and metastasis in
plete remission and the other six had a greater than 75% experimental models, and it can also act as an anti-prolif-
response. A phase II trial of 4-HPR (200 mg/day) was car- erative agent by interrupting the cell cycle, disrupting mi-
ried out for 3 months in OL patients who had not responded totic spindle structures, and inducing apoptosis and
(“de novo” resistance) or who had responded and then re- micronucleation. [13]
lapsed (acquired resistance) to the previous treatment with Small doses of curcumin are taken daily as a spice
natural retinoids. Of 35 patients with retinoid-resistant OL, by the population in many Asian countries. In one epide-
no patient had complete responses and 12 (34.3%) had par- miologic survey, in terms of its dietary use in Nepal,
tial responses to 4-HPR. Nine patients had clinical re- curcumin consumption was found to be approx. 50 mg/day.
sponses within 9 months of stopping 4- HPR. Systemic use In India, where the average intake of curcumin can be as
of 4-HPR with 200 mg/day for 3 months in 35 patients dem- high as 100 mg per day, no toxicities or adverse effects
onstrated partial clinical resolution of OL of 12 pa- have been reported or studied at the population level.
tients.[10] However the doses administered in clinical trials are ex-
pected to be rather higher than those normally consumed

1500 https://www.journal-imab-bg.org J of IMAB. 2017 Jan-Mar;23(1)

in the diet. [14] may help prevent oral cancer from forming in patients with
In spite of reported minor adverse effects, large an oral premalignant lesion.
doses of up to 12,000 mg per day of curcumin were found
to be well tolerated in humans. Therefore, based on the 4.2. Green Tea Polyphenols
safety and toxicity profile, in several clinical trials the Epigallocatechin gallate (EGCG), a major polyphenol
targeted doses for curcumin can be recommended in found in green tea possesses antioxidant and chemo-pre-
between 4,000–8,000 mg to obtain the maximum therapeutic ventive properties. Epigallocatechin gallate (EGCG) shows
effects. [14] very promising results. [11]
In 2010, some clinicians conducted a study on pa- According to one study, 29 out of 59 patients with
tients aged 17-50 years, divided into three groups with 25 oral leukoplakia were randomized to use a mixed tea extract
patients in each. The first group consisted of patients suf- orally as well as a topical tea extract. After the 6-month trial,
fering from leukoplakia, while patients suffering from oral the oral lesions had decreased in size in almost 40% of the
submucous fibrosis or lichen planus, and those in full patients treated, which was associated with a decrease in
health constituted the second and the third groups, respec- proliferation in the treatment group on histopathologic ex-
tively. Evaluation of markers of oxidative stress in saliva, amination (P < 0. 05) [11]
serum in salivary glands (malondialdehyde (MDA), 8-hy-
droxy-22 -deoxyguanosine (8-OHd), and the level of vita- 5. Photodynamic Therapy (PDT)
min C and E was made before administering curcumin to Photodynamic therapy is a non-invasive method of
the patients, a week later, and after recovery. treatment for head and neck tumors and premalignant le-
It was noted that the markers in saliva, serum and sions . [2, 15]
vitamin level increased, whereas MDA and 8-OHd levels It is based on photo-chemical reaction, initiated by
decreased simultaneously in patients suffering from light activation of a photosensitizing drug causing tumor
leukoplakia, oral submucous fibrosis and lichen planus. cell death. It requires the simultaneous presence of a pho-
Considering the results of the Rai et al. study, it can be tosensitizing drug (photosensitizer), oxygen, and visible
assumed that curcumin demonstrates anticancer properties light and it is a non-thermal reaction. [2, 15]
by increasing the levels of vitamins C and E, suppressing The photosensitizer is administered systemically by
the peroxidation of lipids, and preventing DNA damage. intravenous injection or can be topically applied. [2]
[12] After a period to allow the photosensitizer to col-
Some authors observed the reduced size of the le- lect in the target tissue, the photosensitiser is activated by
sions in 10 of the 62 patients receiving topical turmeric/ exposure to low-power visible light of a drug specific wave-
curcumin in oral cancers and leukoplakia, however the re- length. [15]
port is lacking the control group and standard method of Mainly, the light source consists of a portable di-
curcumin preparation. [14] ode laser and the light is transmitted via laser fibers to or
A phase I clinical study performed in Taiwan inves- into the tumor [10]
tigated the potential anti-carcinogenesis activity of Intracellular activation of the photosensitizer drug
curcumin in patients with preinvasive malignant or high- results either in the production of radicals (type I mecha-
risk premalignant conditions.25 patients with recently nism) or the formation of intracellular singlet oxygen (type
resected cancer of the bladder, Bowen disease of the skin, II mechanism), which causes cell death by vascular shut
uterine cervical intraepithelial neoplasia, intestinal meta- down mechanisms and intracellular oxygenation. [15]
plasia of the stomach, or oral leukoplakia, were adminis- The main advantages of PDT are:
tered curcumin in doses of 1,000 to 8,000 mg (500 mg of • Photodynamic therapy is a localized therapy and
synthetic curcumin per capsule, 99% purity) daily for three it has only localized effects as the photosensitizer is selec-
months. Histologic improvement of the premalignant le- tively absorbed by the target tissues.
sions was noted in two of seven patients with oral • Photosensitizing agents have low systemic toxic-
leukoplakia. On the contrary, one of seven patients with ity.
oral leukoplakia developed malignancy despite the treat- • Photodynamic therapy is more economical than ra-
ment. [14] diation therapy and surgical therapy for cancer patients.
It seems that curcumin is a pluripotent pharmaco- • PDT is less invasive, has no long-term side effects
logical agent [13] and may be the new hope for reducing and can be repeated many times at the same site, if needed.
incidence of cancer and precancer. [12] • Photodynamic therapy has excellent cosmetic re-
A trial study in USA (National Cancer Institute) in- sults and the healing process results in little or no scar-
vestigate if metformin hydrochloride works well in prevent- ring.[16]
ing oral cancer in patients with an oral premalignant lesion There are several photosensitizers which have been
(oral leukoplakia or erythroplakia). These lesions can be developed and approved in time: (1) Photofrin; (2) 5-
associated with a higher risk of cancer. Another study also Aminolaevulinic acid (ALA); (3) Verteporfin ;(4) Foscan.
in USA evaluate prevention of oral cancer in patients with [2, 10]
an oral premalignant lesion by using Metformin Hydrochlo- 5-Aminolevulinic acid (ALA)- mediated photody-
ride in combination with curcuminin. They thing that namic therapy (PDT) is a new therapy for the treatment of
Metformin hydrochloride in combination with curcumin oral leukoplakia. [15]

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 5-Aminolevulinic acid is the only photosensitizer ited to the treatment of cancer of the lip and oral cavity. At
which can be given orally or applied topically. All other present, cryosurgery has an extensive application in the
photosensitizers have to be given intravenously. [15] treatment of both benign and malignant lesions in the head
A study was done to determine therapeutic re- and neck region. [17]
sponse to PDT in patients with oral leukoplakia. Twelve It has several advantages including bloodless treat-
patients were selected with lesions at a variety of intraoral ment, a very low incidence of secondary infections, and a
sites. Patients were treated with topically applied 10% ALA relative lack of scarring and pain. [2, 4]
and light from an argon-pumped dye laser. Irradiation was Furthermore, newly rebuilt epithelium is less likely
performed in several (6-8) sessions using light at 635 nm to become corneous again. [1]
wavelength, delivering a total dose of 100 J/cm2 per It can also be used for high-risk group patients like
session. A complete response was obtained in 10 out of those with a pacemaker, the elderly, and those with
12 treated patients. One recurrence was observed during coagulopathies. In addition, it would be the first choice in
6 months. [15] the case of multiple and extensive lesions, areas of diffi-
The photodynamic therapy appears to be a feasible cult surgical access, and areas where esthetics is important.
alternative to conventional therapy of premalignant lesions [17]
of oral cavity. [15] Cryosurgical effectiveness is high and ranges from
At present, PDT is most successful for the superfi- 80% to 100%. The effectiveness depends on adequate freez-
cial lesions of the epithelium such as basal cell cancer, mi- ing time and proper freezing depth. [1]
cro invasive and intraepithelial dysplasias. The maximum The choice of cryosurgical methods in the treatment
depth of necrosis achieved by PDT is at around 1 cm hence of oral leukoplakia depends on the depth, area, and shape
it is not suitable for lesions greater than 1 cm diameter.[16] of the pathological lesion, as well as on access to cryosur-
gical equipment and operator’s experience. [1]
Surgical treatment of oral leukoplakia Available cryosurgery apparatus are classified into
1. Conventional surgery- excision open and closed systems. [2, 4, 17]
Conventional surgery refers to scalpel excision of the Closed-system cryotherapy offers a greater degree of
lesion. [2] temperature control but requires complex, delicate, and ex-
This is followed by a primary closure or secondary pensive equipment. It is performed by direct contact of the
healing in case of reduced mucosal defects or with a trans- cryoprobe onto the lesional surface. Because of the small
position of local mucosal faps or even skin graft in case and flat contact area of the cryoprobe end, closed-system
of large defects. [2] cryotherapy is usually suitable for treatment of uniform,
Conventional surgery may not feasible for extensive smooth-surfaced oral lesions less than 1 cm in diameter. [4,
lesions or those in certain anatomical locations. [3] The as- 17]
sociated morbidity of surgery also makes it less appealing Open-system cryotherapy involves directly applying
for extensive lesions. [3] the cryogen to the lesion with a cotton swab or a portable
The use of a scalpel may induce wide areas of denu- spray apparatus. It is more difficult to maintain a constant
dated mucosa with unfavorable scarring changes and sec- lower temperature in the lesional tissues during the whole
ondary functional alterations as surgical sequelae. [4] treatment period. However, it does not need expensive
It should be noted however that curative surgical re- equipment. Open-system cryotherapy with the spray appa-
section has the potential to be effective as a prophylactic ratus is suitable for treatment of medium and large oral le-
treatment of lesions on the tongue having a tendency to sions with either a smooth or a rough surface. [4]
develop cancer. [4] During cryotherapy the ice crystals are formed in
both extracellular and intracellular fluid leading to the cel-
2. Electrocoagulation lular dehydration, toxic intracellular electrolyte concentra-
Electrocoagulation can be used alone or as an tion, inhibition of enzymes, protein damage. These mecha-
adjuvant to scalpel surgery. [2] Electrocoagulation pro- nisms associated with the thermal shock induce the vacu-
duces thermal damage in the underlying and surrounding olization of cells, their expansion and finally their rupture.
tissue, which causes postoperative pain and oedema, and Also the vascular changes are followed by ischemic necro-
leads to considerable tissue scarring. Postoperative pain and sis of the treated tissue and immunological responses which
oedema are also severe after cryosurgery. [2, 3] will produce the damage of tissue by cytotoxic immune
mechanism. [2]
3. Cryosurgery
Cryosurgery is a method of treatment which in- 4. Laser surgery (excision or evaporation)
volves controlled tissue damage caused by low tempera- The laser surgery has been reported as most appre-
tures. [1] This method locally destroys lesional tissue by ciated in the last 30 years. [2]
freezing in situ [2, 4] Carbon dioxide, neodymium: yttrium-aluminium
- by liquid nitrogen (N) or dinitrogen dioxide (N2O2) garnet (Nd:YAG), argon, and potassium-titanyl-phosphate
[1] (KTP) lasers are used in the management - vaporization or
Arnott, a British physician, was the first person to excision- of oral leukoplakia. [3]
use cryosurgery in the year 1851. Initially, its use was lim- Their precision allows a conservative and site-spe-

1502 https://www.journal-imab-bg.org J of IMAB. 2017 Jan-Mar;23(1)

cific, minimally invasive surgery with sterilization of the sur- focal length), reduces the power and depth of penetration
gical area and minimal intraoperative hemorrhage. These la- of the laser beam (200-400 lm per pass), limiting the destruc-
sers also permit a better postoperative period, with less tion to the epithelium and hence resulting in lesser pain,
swelling and pain and healing with minimal scarring. [4] This swelling and even scarring with better regain of elastic prop-
can be performed even for extensive lesions. [2] erty of the tissue. [4]
Wound healing is excellent because of limited con- As an alternative, the CO2 laser vaporization (ë=10.6
traction; it produces satisfactory mobility of the oral mu- ìm, continuous wave, defocused) is an established proce-
cosa and minimum oral dysfunction. [3] dure that has been in use for more than 35 years. This tech-
Additional advantages of lasers include an optimal nique has been proven to be very effective. [4]
visualization of the surgical area, seal of lymphatic, and Vaporization of tissue with a defocused laser beam
nerve endings which minimizes the chances for neoplastic is, however, not entirely minimally invasive. Horch et al.
cells seeding and the elimination of precancerous fields have shown histologically that thermal laser energy car-
(dysplasia) neighboring the leukoplakia with minimal sur- bonizes superficial parts of epithelium resulting in re-epi-
gical morbidity. [4] thelization being delayed for more than two weeks and the
Comparing different laser techniques, CO2 laser, possibility of healing with scarring. A delay in wound heal-
neodymium: yttrium aluminum garnet (Nd:YAG) laser, and ing can also be an encumbrance for the patient. [4]
potassium-titanyl-phosphate (KTP) there are differences in The laser evaporation technique has a disadvantage,
recurrence rates (34.2%, 28.9%, and 17 %). [2] as no tissue is available for histopathological examination.
The Nd:YAG laser, because of its unique character- [3], which is crucial in the case of dysplasia.[1]
istics (its ability to coagulate and ablate; it is not as pre- The CO2 laser treatment of potential lesions is most
cise a cutting tool as the CO2 laser), has specific advan- efficacious when used in defocused mode. It may be as-
tage in the treatment of large oral vascular malformations. sumed that the heat generated can also destroy deeper-ly-
[18] ing dysplastic cells. [4]
The CO2 laser was one of the earliest gas lasers in-
vented by Kumar Patel of Bell Labs in 1964, and it still CONCLUSION
remains the most useful lasers in oral and maxillofacial/ The degree of epithelial dysplasia is mandatory for
head and neck surgery practice. CO2 lasers are by far the the correct choice of the treatment. In the presence of epi-
highest power continuous wave lasers that are currently thelial dysplasia, surgical treatment is recommended. In
available. They are also very useful in oral surgical proce- cases of absence of dysplasia lesion can be completely re-
dures since the energy is maximally absorbed by water in moved or not. In this case the decision should consider
the oral tissues. [18] clinical factors such as location, size and the patient’s en-
The treatment of oral leukoplakia using CO2 laser gagement in smoking cessation and patient’s cooperation.
can be best obtained by ablation or vaporization of the le- All individuals with leukoplakia, and those who
sion. [4] were treated for it, should be followed-up regularly, regard-
Ablation being done at defocused mode (achieved less of their response to topical or systemic treatment, in-
by moving the laser away from the tissue and beyond its cluding clinical resolution.

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Please cite this article as: Deliverska EG, Petkova M. Management of Oral Leukoplakia - Analysis of the Literature. J
of IMAB. 2017 Jan-Mar;23(1):1495-1504. DOI: https://doi.org/10.5272/jimab.2017231.1495

Received: 25/01/2017; Published online: 26/03/2017

Address for correspondence

Elitsa G. Deliverska
Department of Oral and Maxillofacial surgery, Faculty of Dental Medicine,
Medical University - Sofia, Bulgaria;
1, St. Georgi Sofiiski str., 1431 Sofia, Bulgaria.
E-mail: [email protected],
1504 https://www.journal-imab-bg.org J of IMAB. 2017 Jan-Mar;23(1)