oral potentially malignant lesions review

Squamous cell carcinoma andprecursor lesions: prevention

SA M A N WA R N A K U L A S U R I Y A

Introduction

Major risk factors for oral squamous cell carcinoma

and precursor lesions of the oral cavity are smoking,

use of smokeless tobacco and alcohol misuse. In

specific regions of the world, particularly in some

Asian-Pacific countries, the chewing of betel quid is

an additional risk factor. Human papillomavirus

(HPV) infection is an emerging risk factor for oro-

pharyngeal carcinomas. These risk factors and etio-

pathogenesis are considered in detail by Johnson

et al. (40) in this volume, and in an earlier review

(107). The purpose of this review is to inform oral

healthcare professionals about effective methods for

reducing harm from these etiological agents, and

about care pathways to reduce the burden of oral

cancer by engaging in public health programs or

clinical interventions. These interventions should

mostly be targeted at the high-risk groups who

present in primary care settings with oral potentially

malignant disorders (110). The objective of this

article is to stimulate a debate on effective preventive

measures in clinical practice. This review includes an

overview of both public health measures and targeted

measures that could be undertaken in dental offices

by oral healthcare professionals and that may lead to

control of oral cancer by effectively managing

patients with established risk factors and potentially

malignant disorders (precursor lesions). The current

evidence available on treatment of precursor

lesions in the hope of eliminating future develop-

ment of a carcinoma in the precursor lesion is also

reviewed.

The methods of prevention or interventions dis-

cussed include cessation of tobacco use, moderation

of alcohol use, stopping betel quid use, vaccination

against viruses, dietary intervention, and chemopre-

vention, as well as tertiary prevention measures e.g.

surgery to prevent malignant transformation.

Cessation of tobacco use

The risk for oral cancer in former smokers almost

matches that of never smokers 10 years after cessa-

tion (106), clearly indicating the benefits of stopping

tobacco use. Smoking cessation has been shown to

reduce both the relative risk (20) and lifetime risk (6)

of developing oral and other aerodigestive tract can-

cers. For cancers of the oral cavity and pharynx

together, the cumulative risk for Italian men who

continued to smoke any type of tobacco was 3.3% by

75 years of age, but the risk dropped to 1.4% and

0.5% for men who stopped smoking at approximately

50 and 30 years old, respectively (6). Pooled data

from the Head and Neck Epidemiology Consortium,

based on 17 studies reporting smoking cessation,

confirmed these observations (61). It has been esti-

mated that tobacco cessation, alone could contribute

to the prevention of a substantial proportion of can-

cers at this site.

Smoking cessation is also associated with reversal

of epithelial dysplasia in pre-cancer (64). In India, a

primary prevention trial of oral cancer was under-

taken in Kerala state. A high proportion of subjects

were smokeless tobacco users. When tobacco use was

stopped or reduced substantially, the regression rates

of pre-cancer increased significantly (27).

Community interventions

There is evidence that comprehensive tobacco con-

trol programs including media campaigns, higher

taxes and smoke-free environments can be effective

in changing smoking behavior in adults, but the evi-

dence comes from a heterogeneous group of studies

of variable methodological quality. Bala et al. (2)

performed a systematic review of media campaigns

and reported significant decreases in smoking

prevalence after the Massachusetts and California

38

Periodontology 2000, Vol. 57, 2011, 3850

Printed in Singapore. All rights reserved

2011 John Wiley & Sons A/S

PERIODONTOLOGY 2000

statewide tobacco control campaigns compared with

the rest of the USA. Community interventions as

outlined in the World Health Organization Frame-

work Convention on Tobacco Control represent a

key component of current anti-smoking strategies.

Population-level tobacco control interventions also

have the potential to benefit more disadvantaged

groups (98). Oral health professionals should be

ardent supporters of such public health measures.

They need to engage in debates about important

developments in tobacco control and assume a

leading role in inter-professional activities on control

of oral cancer.

Preventive measures for smokingcessation undertaken in dental practices

There is good evidence that brief interventions by

health professionals can increase rates of smoking

cessation (75). Attempts at encouraging tobacco ces-

sation in dental pratices by have been previously re-

viewed (114). Trials that examined the feasibility of

involvement of dental practices in smoking cessation

confirmed a pivotal role of the team approach in better

outcomes (92). Dentists who implement an effective

smoking cessation program can expect to achieve

cessation rates of up to 1015% each year among

patients who smoke or use smokeless tobacco. The

recommended care pathway is to provide brief

interventions in the dental practice, while utilizing

specialist smoking cessation services to provide addi-

tional benefits, (75). Such schemes should provide

information exchange between the specialist smoking

cessation services and the dental team that could be

valuable for patient follow up.

Ebbert et al. (13) performed a meta-analysis of

randomized trials on interventions for smokeless

tobacco cessation, mostly in US dental offices. The

majority of these behavioral interventions were

undertaken by oral hygienists dentists who hadreceived training in tobacco intervention skills. The

odds ratio for giving up smokeless tobacco use fol-

lowing behavioral interventions that mostly included

an oral examination and feedback, was 1.66 (95%

confidence interval; 1.481.88). Varenicline was also

effective in Swedish users of snus (odds ratio 1.6; 95%

confidence interval; 1.082.36).

Preventive measures in hospital clinics

A number of studies have examined the effectiveness

of tobacco cessation interventions in oral medicine

practices for patients diagnosed with precursor

lesions. For example, Roed-Petersen (78) reported

resolution of leukoplakia following smoking cessa-

tion. Another interventional study in a dysplasia

clinic in London provided brief cessation advice and

utilized a specialist smoking cessation clinic for

intensive interventions and pharmacotherapy. They

achieved a cessation rate of 30% (74).

Methodological issues

For both tobacco smoking and the use of oral

smokeless tobacco, nicotine remains the main

determinant of addiction. For smokers who wish to

quit, effective smoking cessation treatments are

available (112), and every patient diagnosed with oral

pre-cancer or cancer who uses tobacco should be

offered one or more of these treatments.

There are many intervention strategies and poli-

cies for smoking cessation among adults. Data from

many sources confirm that a wide array of effective

smoking cessation intervention approaches and

policies can have a significant impact on improving

smoking cessation rates.

Treatment methods that have been researched and

found to be effective are set out in Table 1. These

summary results are extracted from data published in

Table 1. Evidence-based treatment methods for suc-cessful smoking cessation published in the CochraneDatabase of Systematic Reviews based on publishedmeta-analyses (7, 24, 36, 48, 77, 93, 94, 115)

Type of therapy Number

of trials

Estimated odds ratios

(OR) and 95%

confidence

intervals (CI)

OR CI

Nursing intervention 42 1.28 1.181.38

Physicians advice

Brief advice 17 1.66 1.421.94

Intensive advice 11 1.84 1.602.13

Dentists advice 6 1.44 1.161.78

Counselling 21 1.56 1.321.84

Nicotine replacement

therapy

132 1.58 1.50 1.66

Clonidine 6 1.89 1.302.74

Bupropion 31 1.94 1.722.19

Varenicline 7 2.33 1.952.80

Nortriptyline 4 2.34 1.613.41

Acupuncture 24 1.36 1.071.72

39

Prevention of cancer and precursor lesions

the Cochrane Database of Systematic Reviews (http://

www2.cochrane.org/reviews/), including a number

of meta-analyses. Advice and support from health

professionals (nurses, dentists and physicians) could

increase peoples success in giving up smoking.Intensive group treatment is better than brief advice.

Nicotine replacement therapy aims to reduce

withdrawal symptoms associated with cessation of

smoking by replacing cigarettes with medicinal nic-

otine. The chances of stopping smoking increase by

5070% with use of nicotine replacement therapy.

Nicotine replacement therapy is available as skin

patches that deliver nicotine slowly, and as chewing

gum, lozenges tablets, inhalers and nasal spray, allof which deliver nicotine to the brain via the blood-

stream. Those that deliver nicotine rapidly, (e.g. nasal

sprays), may be used in combination with prepara-

tions that deliver nicotine more slowly. Smokers

attending UK National Health Service Stop Smokingservices are four times more likely to succeed in

giving up and remain as ex-smokers than those who

attempt to quit unaided, on the basis that medication

approximately doubles the chances of quitting, and

behavioral support further doubles the outcome.

Medications prescribed under physicians guidanceas adjuncts to smoking cessation include bupropion

and varenicline, and both have shown promising

long-term results (Table 1). These medications ap-

pear to attenuate the urge to smoke, the negative

effect of withdrawal symptoms, and people find it

easy to quit because smoking loses its appeal. They

have a high affinity for nicotine receptors. In trials

comparing these two therapies, varenicline was

superior to bupropion (odds ratio 2.18, 95% confi-

dence interval; 1.094.08) (14).

Most adult smokers would like to quit, and effec-

tive therapies are now available. The adverse health

consequences of smoking and smokeless tobacco use

could be avoided by improving awareness and by

providing services that are accessible to those at risk.

Tobacco dependency requires targeted therapies

(112), and those with oral precursor lesions constitute

a special group who need assistance in giving up

tobacco use. Providing support for tobacco cessation

through oral healthcare providers could contribute to

saving lives. Why then, is smoking cessation over-

looked when there are opportunities to intervene, as

tobacco use is quite apparent in the oral cavity as

either melanosis, gum disease, or precursor lesions?

Some dentists may view smoking as a lifestyle choice

rather than an addiction that requires treatment.

Others cite a lack of time, training or proper com-

pensation for smoking cessation programs. There are

now excellent online resources on tobacco cessation

interventions for European dentists, and one such

is managed by the Oral Health Network of Tobacco

Use Prevention and Cessation (http://www.tobacco-

oralhealth.net).

Alcohol

Alcohol use is the second most important risk factor

for the development of oral cancer. Ethanol is clas-

sified by the International Agency for Research on

Cancer as a human carcinogen (37). A large number

of cohort and casecontrol studies provide strong

evidence that consumption of alcohol is an inde-

pendent risk factor for oral and pharyngeal cancers

(37). Daily consumption of approximately 100 g of

ethanol above recommended levels increases the risk

for oral and oropharyngeal cancers two- to threefold

compared with the risk for non-drinkers. The risk of

oral cancer increases with the number of alcoholic

drinks consumed per day in a dose-dependent fash-

ion (5). Pooled data from the Head and Neck Epide-

miology Consortium based on 13 studies on alcohol

cessation confirmed the benefits of abstaining or

reducing alcohol consumption (61). The risk is mul-

tiplicative for combined use of alcohol and tobacco.

Some population groups with inherited defects in

metabolism of alcohol may have an inability to break

down acetaldehyde (the carcinogenic metabolite of

alcohol) and may be at increased risk. Oral biofilms

(bacteria) assist in the metabolism of alcohol to

acetaldehyde, and improving oral sepsis and hygiene

among alcoholics may help to reduce local acetal-

dehyde formation and thereby reduce the potential

risk of oral cancer.

Alcohol use has also been shown to be associated

with oral leukoplakia (30), and moreover with malig-

nant transformation from leukoplakia to cancer (86).

There is a controversy as to which types of alco-

holic drinks mostly cause mouth cancer. It is not clear

whether its the alcohol concentration in beverages or

the quantity drunk that contributes to excess risk.

There is no clear evidence that specific alcoholic

drinks, i.e. spirits, wine or beer, have different effects

on oral cancer. Substitution of the type of drink is

therefore not advisable. The most frequently con-

sumed alcoholic beverage in a population is likely to

be associated with the highest risk for that given

population.

If followed, the guidelines in the European Code

Against Cancer (2008), i.e. daily consumption of less

than two drinks for men and one drink for women,

40

Warnakulasuriya

would lead to a significant reduction of cancer risk in

the population (www.cancercode.org/code.htm).

Combating binge drinking would also contribute to

control the reported rising incidence of tongue

cancer noted in young people.

Most people who misuse alcohol require support-

ive care, and those who are dependent require

pharmacotherapy to manage alcohol withdrawal and

medical treatment to prevent relapse. The drugs used

to prevent relapse include disulfiram, acamprosate,

baclofen and naltrexone. The mechanisms of action

of these agents in relapse prevention were discussed

in a recent review by Lingford-Hughes et al. (53).

These drugs should be used as adjuncts to psycho-

social programs. Abstinence is the goal of treatment.

Brief advice and motivational enhancement against

alcohol misuse (Table 2) (70, 84) are effective

healthcare interventions, and the oral healthcare

team is ideally placed to provide these with some

additional training.

Betel quid

In parts of South and South East Asia and in Mela-

nesia, there is a high incidence of oral cancer, and

betel quid use is recognized as a risk factor for the

disease burden in these populations (28). A recent

evaluation by the International Agency for Research

on Cancer concluded that areca nut, the main

ingredient used in betel quid or commercially pack-

aged pan masala, is carcinogenic to humans (38).

Cancers of the oral cavity arise in locations in the

mouth where betel quid and areca nut are kept for

long periods (113). Furthermore, chewing betel quid

without tobacco has recently been shown to increase

the risks of cancer and various oral precursor

conditions (39). A recent meta-analysis of five studies

that controlled for smoking reported an increased

risk among betel quid users for oral leukoplakia (odds

ratio 7.9, 95% confidence interval; 4.314.6) (99). Oral

sub-mucous fibrosis caused by areca nut use is a

debilitating disorder with a significant potential for

malignant transformation. Medical interventions to

manage oral sub-mucous fibrosis in the hope of

preventing oral cancer have been recently reviewed

(42).

Some individuals develop a dependency syndrome

to areca nut (116), and development of an appro-

priate care pathway is required, as for tobacco

intervention, with facilities for treatment and pro-

grams to reduce harm. Only a few studies have been

performed. In a 10-year follow up study in India,

cessation of chewing habits (areca nut and tobacco

use) was reported in 8.7% men and 13.6% women

(26). In a community pilot investigation, Croucher

et al. (12) confirmed that methods identified as

helping tobacco smokers to successfully stop smok-

ing, such as nicotine replacement therapy, can also

be used for Bangladeshi women who chew paan with

tobacco. The neuropharmacology of addiction to

areca nut has not been studied in detail to suggest

suitable pharmacotherapy. The dopaminergic meso-

limbic system is likely to play a central role, as

described in other addictions (53). Further research is

required to characterize which neurotransmitters

modulate the dopaminergic pathway in areca nut

abusers so that medications available to treat addic-

tions or new therapies can be tried. Substitution with

gums that taste of areca may help to reduce craving

in people who experience withdrawal.

Human papillomavirus

Human papillomavirus (HPV), the causal agent for

cervical cancer, is now implicated in causation of

cancers of the oral cavity and particularly the oro-

pharynx (23). Finding HPV DNA in oral and oropha-

ryngeal cancers provides one explanation as to why

people who have no major lifestyle risk factors (to-

bacco and alcohol use) may develop cancer at this

site. The presence of HPV DNA in oral and oropha-

ryngeal cancers adds weight to the hypothesis that

sexual transmission of the virus may be implicated

in the development of oropharyngeal cancer. We

previously reported on the involvement of HPV in

precursor lesions and during progression from pre-

cancer to cancer (15).

Table 2. Brief advice and motivational enhancementagainst alcohol use (70, 84)

Brief advice (delivered by generalists)

Simple structured advice to reduce to sensible or less

risky levels

Motivational enhancement (2030 min)

Structured feedback on personal risk and harm

Emphasis on personal responsibility to change

Clear advice to cut down or abstain

Discussion of options for changing patterns of use

Reinforcement of the patients self-efficacy

*Should be non-judgmental*Express empathy when interviewing and giving advice

41


These findings suggest a strategy to prevent or

reduce the incidence of oropharyngeal cancer by the

introduction of vaccination programs. Two pre-

ventive vaccines [Gardasil (Merck) and Cervarix

(GlaxoSmithKline)], which target high-risk HPV types

16 and 18, are now available. In the UK, human

papillomavirus vaccines are licensed for girls aged

915 years. There is an optimistic outlook for HPV

vaccination, and the research community needs to

provide confirmation on its effect on oral cancer

whether it is as promising as initially demonstrated

in reducing the incidence of cervical cancer. The

effect is expected to be greatest in women who have

not yet been exposed to HPV. Vaccination before

adolescence makes it more likely that the recipient

has not been exposed to HPV. Large prospective ran-

domized trials are required to document the clinical

effectiveness of HPV vaccination to control oral and

oropharyngeal cancer. It has been suggested that HPV

immunization be offered to boys to counter the

increased incidence of HPV related oral cancer

(The Guardian, 20 February 2011; http://www.

guardian.co.uk/science/2011/feb/20/boys-human-

papilloma-virus-jabs?INTCMP=SRCH).

Diet and nutrition

Most foods that are protective against cancer of the

mouth and pharynx are of plant origin. Based on a

recent evaluation by the World Cancer Research

Fund (118), there is convincing evidence that

higher consumption of non-starchy raw vegetables

including cruciferous and green leafy vegetables

and non-starchy tubers (e.g. carrots) may protect

against cancers of the upper aerodigestive tract,

including the mouth and pharynx (summary odds

ratio 0.72, 95% confidence interval: 0.630.82).

There is evidence that fruits (particularly citrus

fruits) may also provide protection (summary odds

ratio per 100 g per day 0.72, 95% confidence

interval: 0.590.87. Carotene-rich vegetables such as

broccoli, carrots and peppers (capsicums) or green

leafy vegetables appear to provide greater protec-

tion than vegetables lacking b-carotene. Thus, it isclear that cancers of the mouth and pharynx and

probably also the wider range of malignant neo-

plasms that affect the aerodigestive tract can be

prevented by consuming a diet rich in antioxidants,

notably fresh vegetables and fruits (71, 108). This

should be coupled with a reduction in the levels of

consumption of processed, preserved and smoked

foodstuffs, as well as roasted and grilled foods. The

message at the heart of the UK 5 A DAY program to eat at least five portions of a variety of fruit and

vegetables each day (total 400 g day) is consis-tent with dietary recommendations around the

world, including those from the WHO (120), and

will contribute to a reduction of oral cancers in the

community.

Chemoprevention

Chemoprevention attempts to reduce cancer inci-

dence by prescribing pharmacological agents or by

dietary supplementation using vitamins, minerals,

trace elements and other bioactive substances.

Long-term supplementation for a median period of

6 years with either a-tocopherol (50 mg day) orb-carotene (20 mg day), or both supplements in 409subjects who smoked did not prevent oral leuko-

plakia (50). The prevalence of leukoplakia (5.9%) in

those receiving either supplement was similar to

population estimates.

Trials on the use of chemopreventive agents for

non-surgical treatment of oral leukoplakia have been

previously reviewed (57, 58, 76), and summary out-

comes are given in Table 3 (4, 9, 10, 17, 21, 22, 34, 41,

43, 44, 54, 56, 60, 66, 73, 80, 85, 89, 91, 95, 96, 100, 101,

121). Primary outcomes of interest are clinical reso-

lution of precursors and preventing malignant

transformation. Dietary supplements that have been

investigated for the treatment of oral leukoplakia

include vitamin A and retinoids (e.g. 13-cis-retinoic

acid, isotretinoin, fenretinide) and their analyses,

used either topically or systemically, as well as

b-carotene and a-tocopherol. Follow-up periods havenot been long enough to estimate the possibility of

malignant transformation, and recurrence of pre-

cancer after discontinuation of supplements appears

to be a common finding in these trial results. Fur-

thermore, toxicity is reported with many agents

used in chemoprevention. A critical review of pub-

lished chemoprevention studies on oral leukoplakia

noted number of inadequacies in the trial designs

(68, 82). Based on one small randomized controlled

trial, the use of oral lycopene over a period of

5 months appears to be effective (91). Even aggres-

sive antioxidant treatment combinations have so far

not been found to be effective in reversing advanced

pre-malignant lesions of the oral cavity and oro-

pharynx, suggesting an urgent need for innovative

approaches (108).

More recently, non-steroidal anti-inflammatory

drugs (NSAIDs) have received attention as potential

42

Warnakulasuriya

Table 3. Chemopreventive trials for oral leukoplakia

Study Therapy Dose Number of

patients

Clinical

resolution (%)

Follow-up

(months)

Recurrence progression

(%)

Sankaranarayanan

et al. (80)

Systemic

retinyl acetate

300,000 IU 42 52 12 67

Stich et al. (95) Systemic

retinol

200,000300,000 IU 21 57 12

Silverman et al. (89) Topical retinol 600 000 IU 16 44 218 0

Shah et al. (85) Topical

isotretinoin

310 mg day 11 28 6 18

Koch (43) Analogues of

retinoic acid

70 mg 75 43 264 3

Koch (44) Etretinate 45 71

Toma et al. (101) Isotretinoin 0.21.0 mg kg 14 36

Chiesa et al. (9) Fenretinate 200 mg day 80 95 9 years 5

Lippman et al. (55) Fenretinide 200 mg day 35 34 3 22

Hong et al. (34) Isotretinoin 12 mg kg 24 67 6

Epstein et al. (17) Topical

tretinoin

0.05% gel 26 27 23 40

Piatelli et al. (73) Topical

isotretinoin

1% 10 10 48

Garewal et al. (22) b-carotene 60 mg day 24 52 6 18

Toma et al. (100) b-carotene 90 mg day 23 26 7 5

Sankaranarayanan

et al. (80)

b-carotene 360 mg 46 54 12 5

Garewal et al. (21) b-carotene 60 mg day 50 4 18 17

Singh et al. (91) Lycopene 48 mg 58 2555 5 0

Benner et al. (4) a-tocopherol 400 IU x2 day 43 23 6 7

Malaker et al. (60) b-carotene orretinoic acid

30 mg x4 day10 mg x3 day

18 33 24 16

Stitch et al. (96) b-caroteneb-carotene +

vitamin A

30 mg x2 week90 mg x2 week

50,000 IU

27

51

15

28

6

Kaugars et al. (41) b-carotene +a-tocopherol +

vitamin C

30 mg day800 IU

1,000 mg

79 56 9 9

Lippman et al. (56) b-carotene +isotretinoin

30 mg day0.51.5 mg kg

33

26

45

92

28 8.5

Zoller (121) b-carotene +a-tocopherol +

vitamin C

75 mg

100 mg

1,000 mg

24 98 3

Nagao et al. (66) b-carotene +vitamin C

10 mg

500 mg

46 25 24 6

43


chemopreventive agents. Sulindac and celecoxib are

effective in promoting regression in high-risk indi-

viduals with adenomas in the large bowel, but

important concerns exist regarding cardiovascular

toxicity associated with selective COX-2 inhibitors. A

few years ago, a cyclooxygenase inhibitor in the form

of an oral rinse (ketorolac) was used in a randomized,

double-blind, placebo-controlled trial (65). Fifty-

seven subjects were enrolled, and complete or partial

response was observed in 30% of subjects for

ketorolac and 32% for the placebo, leading to the

conclusion that ketorolac rinse as tested had no sig-

nificant effect. The authors argued that it may be

necessary to reformulate the agent to enhance pen-

etration of the molecule through the keratin layers

(65). In a phase II randomized controlled trial, cel-

ecoxib at 100 or 200 mg twice daily was ineffective at

controlling oral pre-malignant lesions (69). In an-

other pilot study on 22 subjects, the effectiveness of

celecoxib on oral pre-malignant lesions after being

on the drug over a period of 12 months was reported.

Among compliant subjects, eight of 11 biopsies (73%;

P = 0.0703) showed an improvement in the degree of

dysplasia after 12 months of theraphy (117). These

landmark studies, although their results are contra-

dictory, are very important as they provide proof-

of-concept for experimentation on the use of active

chemopreventive agents in high-risk pre-cancers to

prevent the development of oral cancer. However, a

range of difficulties encountered in clinical trials

suggest that the evidence of the use of chemopre-

vention is not yet strong for oral cancer. Further

clinical trials on inhibition of COX-2 using ketorolac

as an oral rinse, and oral pioglitazone, a drug that is

commonly used to treat type II diabetes, are under

way or have been completed (http://www.cancer.

gov/clinicaltrials).

Topically applied bleomycin (0.51% dissolved in

dimethyl sulfoxide), a cytotoxic agent used in can-

cer therapy, has been used in two trials for treat-

ment of oral leukoplakia (16, 29). Resolution of

leukoplakia and reversal of dysplasia were reported.

In one of the studies, two of the 19 treated cases

transformed to cancer. A number of adverse reac-

tions may occur with bleomycin, including stoma-

titis, erythema, vesiculation and hyperpigmentation

of the skin.

Photodynamic therapy

Photodynamic therapy uses light to activate a

photosensitizing agent in the presence of oxygen to

cause localized photodamage and cell death. At

present, portable diode laser systems are predomi-

nantly used. A number of photosensitizers have

been advocated, including porphyrin derivatives,

5-aminolevulinic acid and temoporfin. Technical

aspects of this treatment have been discussed in

reviews by Konopka & Goslinski (45) and Kubler

(46). Photodynamic therapy with orally or topically

administered 5-aminolevulinic acid has been used

for the treatment of oral leukoplakia. The regression

of leukoplakia or clinical improvement to less

dysplastic states in partially responsive cases has

been reported (8, 18, 47, 87, 102). Significant

side-effects are prolonged photosensitivity,

particularly after the use of intravenous photosen-

tisizers, mucosal burns, and scarring and hyper-

pigmentation.

Surgical intervention

Some experts in the UK routinely advise excision of

any white patch with a diagnosis of leukoplakia (C.

Scully, Eastman Dental Hospital, London, personal

communication) on the basis that some already

contain or will transform to cancer, and one cannot

reliably estimate which ones do or will, not least as

biopsies often only sample a small part of many

lesions. A recent systematic review (62) examined

14 non-randomized studies (1, 3, 11, 25, 31, 32, 35,

49, 51, 59, 63, 79, 83, 88, 90, 97, 103, 104) that

compared surgical excision of oral leukopla-

kia epithelial dysplasia vs. no treatment. Theyfound a considerably higher malignant transforma-

tion rate among the lesions that were not excised

than for those that were excised (14.6% vs. 5.4%;

P = 0.003). The authors concluded that excision of

dysplastic lesions significantly decreased the risks of

transformation but did not completely eliminate

that risk. The results of this meta-analysis should be

viewed with caution due to the heterogeneity of the

studies: Of the 14 studies included, only five of the

publications specified surgical excision, periods of

follow-up were variable, and the rates of malignant

transformation in the various studies ranged from

0% to 37%. Some of the studies included by the

authors we believe do not appear to satisfy the

criteria for selection as the method of treatment

was not specified in few of the original publications

(11, 35), and in one of them was limited to a

medical intervention (49). The authors commented

on the distinct lack of randomized controlled trials

examining different surgical techniques or a con-

44

Warnakulasuriya

siderable lack of follow-up studies. Table 4 lists

some of the relevant studies (1, 3, 25, 32, 59, 63, 79,

83, 97) undertaken, showing the range of outcomes

following surgery or no treatment. The study by

Coredero et al. (10) that included only three sub-

jects was excluded. A group from the Netherlands

reported benefits of laser surgery in oral leukoplakia

in that recurrences following treatment were far

fewer compared with knife excision (103). Whether

we can prevent malignancy by treating precursor

lesions remains an open question. This is one of the

most important problems in oral medicine (33) and

requires further research.

The natural history of oral leukoplakia the most

common precursor lesion encountered in the oral

cavity remains unclear (67). At present, the ab-

sence or presence (and the grade) of oral epithelial

dysplasia remains the most useful guide to our

management of leukoplakia (109). The presence of

oral dysplasia significantly increases the rate of

transformation to cancer, and this may increase

with the grade (62). It is therefore argued that

treatment of dysplastic lesions may prevent cancer

development in high-risk patients with oral leuko-

plakia. Currently, there is debate as to how we

should manage oral leukoplakia or other precursor

lesions as none of the available treatments (medical

or surgical) have sufficiently being researched to be

evidence-based.

Screening

Population screening provides a means of reducing

cancer incidence (prevention). Benefits have not

been widely evaluated for oral cancer. The concept

underpinning screening is based on the premise that

earlier detection of the asymptomatic phases of oral

precursor will allow modification of risky behaviors

and use of other clinical interventions in an attempt

to prevent cancer (111). Screening high-risk groups

and opportunistic screening where people have good

access to dental care will allow earlier case detection

(105). In addition to visual screening, a number of

adjunctive tests are available (19), but these have

limitations in predicting which suspicious lesions

may progress to cancer. However, new technology is

encouraging dentists to perform thorough systematic

oral cavity examinations (52).

Strong evidence to support any national screening

program is still lacking, but one randomized trial in

users of tobacco and alcohol has shown a significant

reduction in mortality from oral cancer in a screened

population compared to deaths in the control group

(mortality rate ratio 0.66, 95% confidence interval;

0.450.95) (81). Screening for precursor lesions and

their effective management could lead to a reduction

in the incidence of cancer in the screened popula-

tion, and thereby contribute to the control of oral

Table 4. Selected follow-up studies showing outcome of surgical excision or no intervention for cases of oral leu-koplakia or epithelial dysplasia

Study Country Mean

follow-up

(years)

Total cases Percentage with malignant

transformation

Excised Followed-up Excised Followed-up

Holmstrup et al. (32) Denmark 6.8 89 147 12 4

Vedtofe et al. (104) Denmark 3.9 61* 5

Arduino et al. (1) Italy 4.6 128 74 9 4

Schepman et al. (83) The

Netherlands

2.5 39 79 20 15

Lumerman et al. (59) USA 1.5 44, 16

Mincer et al. (63) USA 8.0 20 22 15 9

Saito et al. (79) Japan 4.0 75 51 1 8

Gupta et al. (25) India 8.5 0 426 2

Sugar & Bancozy (97) Hungary 23 18 306 0 6

Bancozy & Csiba (3) Hungary 3.6 45 23 2 34

*Includes five cases of oral lichen planus.Includes only oral dysplasia cases.Follow up date based on a pathology database: authors unclear whether completely excised or not.

45


cancer (119). Community-oriented screening pro-

grams and communication on signs and symptoms

and risk factors also increase public awareness and

knowledge of oral cancer (72).

Conclusions

The findings of this review suggest that interventions

to change the health behavior of people at risk of oral

cancer require an educational as well as a personal-

ized approach. Those at risk should be identified by

oral health professionals during regular dental visits

and continued support should be provided after the

initial intervention. The most important steps of

interventions are discouraging young people from

taking up tobacco use, and support for cessation of

tobacco use for those who cannot do so without

professional support. Given the strength of the evi-

dence that ex smokers significantly reduce their

cancer risks, oral health professionals must include

tobacco cessation services as part of routine care,

particularly for those with oral precursor lesions.

Several other preventive measures, e.g. reducing

harm from betel quid use, moderating alcohol habits

and improving oral hygiene health, are also impor-tant in appropriate settings. An ideal chemopreven-

tive agent remains to be discovered. Future research

is required to evaluate surveillance of precursor le-

sions, and less invasive and more effective treatment

protocols are required to prevent cancer development

in subjects with precursor lesions.

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