University J Dent Scie 2015; 1(2) : 49-54

ABSTRACT : Management of potentially malignant disorders such as leukoplakia depends onearly interception &prevention of malignant transformationwhich includes several factors such as age of patients, systemic factors ,history of habits ,size & site of lesion ,its type & clinical features ,natural history & histopathological features .This is achieved by habit counseling for tobacco dependence and use of chemo preventive agents after diagnosis of leukoplakia. Even though numerous manuscripts have dealt with management of oral leukoplakia ,still there is lack of a proper protocol which will aid in appropriate management of oral leukoplakia. Linking all these considerations we hereby aim to propose guidelinesfor appropriate management of oral leukoplakia in Indian scenario.

1 2 3 4

1 2,3,4Department of Oral Medicine and Radiology, Department of Oral Pathology ,

SGT Dental College and Hospital, Budhera, Gurgaon, Haryana, India.

Renu Tanwar, Aparna Dave, Manpreet Kalra, Pulin Saluja

INTRODUCTION : Leukoplakia is a potentially malignant

disorder affecting oral cavity especially in males of middle

aged1.Establishing the clinical diagnosis of leukoplakia,

followed by histopathologic analysis,leads to consideration

of the appropriate clinical management which should be

designed according to the anticipated clinical or biologic

behavior. Balancing the lesional qualities with treatment

modality and associated morbidity becomes the major clinical

decision. With such considerations in mind, a wide choice of

treatments has been used, ranging from those which are

locally directed to others which are systemic. In the absence

of histologically demonstrated dysplastic changes, careful

and routine follow-up observations of leukoplakia may be

appropriate in conjunction with elimination of any risk-

associated behavior or habits. In order to conduct treatment

for OL, the degree of epithelial dysplasia may be assessed. In

the presence of moderate or severe epithelial dysplasia,

surgical treatment is recommended. However, OL presenting

low to moderate malignant risk may be either completely

removed or not, and the decision should consider other factors

such as location, size and, in the case of smokers, the patient's

engagement in smoking cessation. This manuscript

emphasizes on non-surgical management of oral leukoplakia

in Indian scenario.

MANAGEMENT PROTOCOL : Management depends

onearly interception &prevention of malignant

transformationwhich includes several factors such as age of

patients, systemicfactors ,history of habits ,size & site of

lesion ,its type & clinical features ,natural history &

histopathological features .This is achieved by habit

counseling for tobacco dependence and use of chemo

preventive agents after diagnosis of leukoplakia. Even though 1,2,3,4numerous manuscripts have dealt with management of

oral leukoplakia,still there is lack of a proper protocol which

will help in managing oral leukoplakia.Linking all these

considerations we hereby aim to propose guidelines which are

as follows(FIGURE 1)

Figure 1: Flow diagram for management of oral leukoplakia.

CLINICAL EXAMINATION : Proper clinical examination

should be done on the day of reporting of the lesion ; type,

size and location of lesion should be carefully recorded. Low

NON-SURGICAL MANAGEMENT OF ORAL LEUKOPLAKIA IN INDIAN SCENARIO

Journal of Dental Sciences

University

Key Words : Leukoplakia, Lycopene, Retinoids, Bleomycin.

Source of support : NilConflict of interest : None

Review Article

49

risk lesions are classified as size less than 2cms,homogenous

in clinical form and site other than floor of mouth and lateral

border of tongue. High risk lesions are classified as size more

than 2cms,non homogenous in clinical form and site as floor 4.of mouth and lateral border of tongue

ELIMINATION OF RISK FACTORS : such as tobacco

abuse, superimposed candida infection over the lesion

especially in cases of nonhomogenous leukoplakia.

Habit counseling :Counseling alone or counseling with

medication that is being used for tobacco cessation should be

started on day of reporting of the lesion. Significantly high

continuous abstinence rates are seen with the medications as

compared to the counsell ingalone,that is why

pharmacotherapy should be initiated at earliest in cases of

tobacco cessation.(TABLE 1).Pharmacotherapy has to be

initiated at least a week before the quit date for better results.

Table 1 : Drugs used in tobacco dependence.

COUNSELLING : Counselling delivered by physicians and

other professionals significantly increases quit rates over self-

initiated strategies.Even a brief (3-minute) period of

counseling to urge smoker to quit results in smoking cessation

rates of 5-10%.National cancer Institute, USA has formulated

brief strategies to help the patients willing to quit and this 5,6 includes a “5A”(ask, advise, assess, assist and arrange)

University J Dent Scie 2015; 1(2) : 49-54

based intervention in a primary care set up.

i. “ASK” the patients about tobacco use and identified at each

visit. Tobacco use status is queried and documented, and general

and vital informations are obtained.

ii. “ADVICE” to the patient should be clear, strong and

personalized according to the patient's current health/illness,

motivation level or impact on children in the household.

iii. “ASSESS” the willingness of the patient to quit.

Provide motivational assistance to those unwilling to quit

and provide additional information in special situations such as

adolescence and pregnancy.

iv. “ASSIST” the patient with a quit plan. Set a quit date within

the next two weeks. Patient is advised to tell friends, family and

co-workers about quitting and request understanding and

support. Anticipate challenges to quit attempt and educate

about nicotine withdrawal symptoms. Remove all tobacco

products from environment and avoid places associated with

smoking. Provide practical counselling(problem solving and

skill training). Total abstinence is essential. If the patient had

past quit experiences, identify what helped and what

hurt.Anticipate triggers or challenges in upcoming attempts.

Alcohol use to be minimized and tell the patient about risk of

relapse if he/she continues to drink. Encourage housemates

to quit smoking or not smoke in subject's presence. Provide intra

treatment social support and help to provide extra treatment

social support. Recommend intensive treatment in the form of

pharmacotherapy for those willing to quit.(TABLE 1).Provide

supplementary materials, which is culturally, racially

educationally and age appropriate for the patient.

v. “ARRANGE” for follow up contact. Timing of the first

contact should be soon after the quit date and the second follow

up depends on physician preference preferably within the first

month of quit date. Congratulate those who have succeeded to

quit smoking. If failed, identify the cause and be supportive.

Identify problems and anticipate future challenges. Consider

referral to more intensive treatment.

3.REGRESSION IN SIZE :Clinical examination is repeated

after 2-3weeks to assess the regression in size of lesion in low

risk as well as high risk leukoplakia.After 2-3 weeks of habit

cessation, if there is regression in size of leukoplakia than follow

up is done initially every three months followed by every 6-12

months.

4.BIOPSY : Biopsy is mandatory in cases of high risk lesion or

low risk lesion which is not regressing in size even after habit

cessation6. Excisional biopsy is advisable in cases less than

2cms in size irrespective of clinical form of the lesion .In cases

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which show no signs of dysplasia ,then conservative

treatment is advised irrespective of clinical form of the lesion

.In cases of mild moderate or severe dysplasia ,both

conservative and surgical treatment are advised.

CONSERVATIVE TREATMENT : Conservative

treatment includes use of chemopreventive agents such

asvitamins, green tea, lycopene, protease inhibitor and anti-

inflammatory drugs .

Chemoprevention can be defined as the use of specific

natural or synthetic chemical agents to reverse,suppress,or

prevent carcinogenesis before the development of invasive

malignancy.

Sporn(1976)was 1st to coin cancer chemoprevention concept

& stress intervention at earliest stages of carcinogenesis.2,7 Wattenberg (1985) has classified chemopreventive agents

into three broad categories (Figure 2):

1) Inhibitors: preventing the formation of carcinogens. E.g.

Endogenous formation of N-nitroso carcinogens is inhibited

by ascorbic acid and tocopherol.

2) Blocking agents: blocking agents that prevent the

reaction of carcinogens with cellular targets E.g. Aryl alkyl

isothiocyanates.

3) Suppressing agents: that inhibit the promotion and

progression stages of carcinogenesis E.g. Retinoids and

carotenoids, anti-inflammatory drugs, protease inhibitors.

Figure 2: Mechanism of chemoprevention in oral

premalignant disorders.

Wattenberg described the following mechanisms of cancer

protection bychemopreventiveagents :

1. Prevent carcinogen formation.

2. Block carcinogen action.

a. Reduce metabolic activation

b. Increase detoxification (cytochrome P-450, conjugation)

3. Reduce free radical related cellular damagei.e.antioxidants

4. Enhance error-free DNA repair.

5. Suppress cancer expression (reversible)

a. Oncogene control

b. Cellular differentiation

6. Enhance immune surveillance.

M E C H A N I S M O F A N T I O X I D A N T S I N

CHEMOPREVENTION OF ORAL LEUKOPLAKIA 8 (Figure

3):

Figure 3: Mechanism of antioxidants in oral leukoplakia.

1) IMMUNOSURVEILLANCE 8: The development of

cancer cells in the organism stimulates a potent immune

response that locates the cancer cells and destroys them. This

process would involve signals, sent out by the developing

cancer, that can be interpreted by the host's immune system,

which then produces cells to destroy the cancer and sends them

to the cancer site or sites. These immune cells are capable of

elaborating cytotoxic chemicals that can infiltrate and destroy

the cancer cells.Examples of these agents are tumour necrosis

factor alpha carried by macro-phages and mast cells, and tumour

necrosis factor beta,carried by lymphocytes. The cytotoxic

macrophages,mast cells and lymphocytes have the capability of

recognising the tumour site and ``homing in'' on it.This

immunosurveillance was found to been enhanced by anti-

oxidant micronutrients.The anti-oxidant micronutrients, such as

alpha toco-pherol and beta carotene, have been shown to

enhance the production and activity of cytotoxic immune

cells,carrying cytokines that can destroy cancer cells. (Figure 3)

2) MOLECULAR GENETIC MECHANISM 8 : Anti-

oxidant nutrients have been found to enhance the expression of

``wild type'' p53, the well-known cancer suppressor gene

product and to diminish the expression of mutant p53, the

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oncogene expressed in a large number of malignant tumours ,

including squamous cell (epidermoid) carcinoma of the

mouth. Anti-oxidant nutrients, such as beta carotene, were

also found to depress the expression of other oncogenes, such

as H-ras in the hamster buccal pouch carcinoma model .It

appears that anti-oxidant nutrients can inhibit, prevent, or

regress experimental cancer through control of the p53

mechanism. The cancer suppressor gene p53 is stimulated and

its expression enhanced, while mutant p53 and other

oncogenes are dysregulated and their expression

diminished.There is experimental evidence that anti-oxidant

nutrients, such as beta carotene, stimulate some ̀ `heat shock''

proteins such as hsp 70 and hsp90 . Heat shock proteins and

other proteins, possibly G proteins, may act as signals to turn

on the p53 tumour suppressor system and this may be a major

mechanism for the anticancer action of antioxidant nutrients.

The relationship of heat shock proteins to the p53 system has

been demonstrated .(Figure 3)

8 3) ANGIOGENESIS INHIBITION : Another anticancer

mechanism of anti-oxidant nutrients is probably their action

on tumourangiogenesis.Vitamin E, b carotene, and

glutathione have all been found to inhibit tumour

angiogenesis in the hamster buccal pouch carcinogenesis

model.It is proposed that the proliferating cancer cells

produce cytokines or chemical mediators that stimulate the

proliferation of endothelial cells to form an extensive vascular

supply to nourish the developing tumour. If the blood supply

to the tumour did not develop, the tumour growth would be

significantly inhibited.Potent angiogenic agents is TGF-á, a

cytokine found in significantly increased amounts in

experimental oral cancer . Both vitamin E and glutathione

inhibit TGF-á expression as one aspect of their inhibition of

angiogenesis in the hamster experimental cancer model and

their inhibition of carcinogenesis .It is anticipated that other

angiogenic agents will also be found to be inhibited by anti-

oxidant nutrients. (Figure 3)

8 SYNERGISM OF ANTIOXIDANTS : Mixtures of anti-

oxidants were far more potent in experimental cancer

prevention than the individual components of these mixtures .

This may have to do with the fact that their optimal activity

may occur at different oxygen tensions and can be most

effective against clones of cancer cells with differing

metabolic patterns.(Figure 3)Vitamins such as vitamin A , C

and E act synergistically to enhance individual action to

achieve antioxidant action.

SELECTIVITY 8 : The important concept of selectivity of

antioxidants in destroying cancer cells and leaving normal cells

unaffected appears to be related to the fact that these agents

actually penetrate into cancer cells and do not penetrate through

the cell membrane of normal cells.The cancer cells have a

membrane defect which allows this. This penetration has been

clearly demonstrated by the use of beta carotene and vitamin E in

liposomes.(Figure 3)

Chemopreventive agents broadly grouped as :

1) Antioxidants such as

a) Carotenoids – retinoids, â- carotene,lycopene.

b) Vitamin C

c) Vitamin E

2) Protease inhibitors

3) Green tea

4) NSAIDS

Antioxidants in oral leukoplakia:The definition proposed by

panel on dietary antioxidants & related compounds of the FOOD

and NUTRITION BOARD as a dietary antioxidants is a

substance in foods that significantly decreases the adverse

effects of reactive oxygen species,reactive nitrogen species,or

both on normal physiological function in humans8.These are the

substances or agents that scavenge reactive oxygen metabolites,

block their generation or enhance endogenous antioxidant

capabilities.

Endogenous Antioxidants:They exist in both the aqueous and

membrane compartment of cells and can be:

• Enzymes includes Cytochromes oxidase system,

Superoxide dismutase (SOD), Catalase, Glutathioneperoxidase,

Peroxidase.

• Non-enzymes includes lipid phase and aqueous phase

which are as follows :

a) Lipid phase

• - Tocopherol(Vitamin E)

• - carotene(Vitamin A precursor)

b)Aqueous phase

• Ascorbic acid(Vitamin C)

Vitamins such as vitamin A ,C and E act synergistically to

enhance individual action to achieve antioxidant action.

Role of vitamin A :Vitamin A is required in the normal pathway

of epithelial cell differentiation. Free-radical reactions can cause

changes in enzymatic functions and DNA mutations, increasing

the risk of developing malignant cell lines. Reducing free

radicals using antioxidants, such as vitamin A, may prevent such

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cellular changes .An association between vitamin A

deficiency and the enhanced susceptibilitY to carcinogenesis

was reported with an increased risk for developing different

epithelial carcinomas of the lung, colon, pharynx, larynx, and

esophagus9. Natural and synthetic compounds with vitamin-

A activity and inactive synthetic analogues of vitamin-Aare

collectively termed as retinoids.The most biologically,

naturally occurring retinoid is all-trans retinol also called

vitamin-A.Vitamin A, also known as retinol, is an alcohol that

can be converted into an aldehyde (retinal) or retinoic acid.â-

IONONE RING is required for biological activity of vitamin

A. Several provitaminsare present in yellow and dark green

leafy vegetables and fruits such as carrot, mangoes, apricot,

collard greens and broccoli.They are collectively known as

the carotenoid pigments or carotenes.The most widely

occurring and biologically active is-carotene. Epstein and

Gorsky10,11used 0.05% tretinoin gel thatwas applied

topically 4 times per day for the management of nonmalignant

oral white lesions in 26 patients (17 men and 9 women) with a

mean age of 62 years.The vitamin A acid gel was applied

locally for a mean of 3.5 years in patients who experienced

clinical improvement.Although a complete clinical remission

was reported in 27% of patients, a partial response was noted

in 54% of patients, and clinical recurrence was experienced in

about 50% of patients after the topical treatment was

discontinued. Side effects of only a localized soreness were

reported by only 19% of patients.

Lycopene :Lycopene provides the familiar red color to tomato

products and is one of the major carotenoids in the diet.

Lycopene lacks the beta-ionone ring structure and is therefore

devoid of pro-vitamin A activity . Its biological effects in

humans have therefore been attributed to mechanism other

than vitamin A.12Two major hypotheses have been proposed

to explain the anticarcinogenic and anti atherogenic activities

of lycopene13:

• Non oxidative and

• Oxidative mechanisms

NON OXIDATIVE MECHANISM :

ANTIPROLIFERATIVE AND PRODIFFERENTIATION

ACTIVITIES 13 : Lycopene has been found to inhibit

proliferation of several types of cancer cells including those in

breast, lung and endometrium.Lycopene is hypothesized to

suppress carcinogen-induced phosphorylation of regulatory

proteins such as p53 and Rbanti oncogenes and stop cell

division at the Go-G 1 cell cycle phase.

2)HYPOCHOLESTEROLEMIC EFFECTS13:Lycopene has

been shown to act as a hypocholesterolemic agent by inhibiting

macrophage 3- hydroxy-3-methyl glutaryl co-enzyme A

(HMGCoA) reductase, the rate-limiting enzyme in cholesterol

synthesis. These observations have implications for both heart

disease prevention and on the process of carcinogenesis. Cancer

cells have abnormal cholesterol biosynthetic pathways that are

resistant to down regulation by cholesterol, and famesylation is a

key process inoncogene activation. Supplementation with

carotenoids like lycopene may help to prevent common forms of

cancer.

ANTIOXIDATIVE ACTIVITY13 : Oxidative stress is

recognized as one of the major contributors of increased risk of

cancer and in chemical assays, lycopene is the most potent

antioxidant among various carotenoids Lycopene can trap

singlet oxygen and reduce mutagenesis. Singlet -oxygen

quenching ability of lycopene is twice as high as that of beta

carotene and 10 times higher than that of alpha tocopherol .

Mechanism of Quenching of reactive Oxygen by lycopene14

:The quenching of O2 by lycopene and other carotenoids can

occur through physical or chemical means. Physical quenching

predominates and leaves the carotenoid intact, whereas chemical

quenching is responsible for the decomposition of the carotenoid

(bleaching). Physical quenching involves the transfer of

excitation energy from O2 to the carotenoid, thereby producing

ground state oxygen and a carotenoid in the excited triplet state.

The excess energy is dissipated as heat through rotational and

vibrational interactions with the surrounding solvent and

structures . The regeneration of the ground state carotenoids

allows it to again function as a catalyst and undergo additional

cycles of I O2 quenching. The quenching capacity of carotenoid

depends primarily on the number of conjugated double bonds,

which accounts for the exceptionally high capacity exhibited by

lycopene compared with many other carotenoids.

CONCLUSION : Several clinical trials have investigated the

treatment of OL with use of supplements. Although the

administration of retinoic acid and beta-carotene has some

efficacy to resolve OL, the studies were based on small samples

and short periods of follow-up. Given the side effects and

counter-indications of antioxidizing agents, with the exception

of lycopene, the use of agents requires careful control.It can be

concluded that, although some treatments may be effective in

healing oral leukoplakia they do not seem to be able to prevent

relapses andmalignant change. For this reason, oral

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leukoplakiasneed to be regularly followed up by the clinician,

regardless of their response to topical or systemic treatment,

including clinical resolution.

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CORRESPONDANCE :

Dr. Renu Tanwar,

Department of Oral Medicine and Radiology,

SGT Dental College and Hospital, Budhera, Gurgaon, Haryana,

India,

E-mail : renuomdr@gmail.com.

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