NON-SURGICAL MANAGEMENT OF ORAL … Tanwar, Aparna Dave, Manpreet Kalra, Pulin Saluja INTRODUCTION: Leukoplakia is a potentially malignant disorder affecting oral cavity especially
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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
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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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University J Dent Scie 2015; 1(2) : 49-54
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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University J Dent Scie 2015; 1(2) : 49-54
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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University J Dent Scie 2015; 1(2) : 49-54
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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University J Dent Scie 2015; 1(2) : 49-54
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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