Oral cancer Prevention Potter Lodi

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REVIEW ARTICLE

Management of potentially malignant disorders: evidenceand critique

Giovanni Lodi1, Stephen Porter2

1Unita`di Medicina e Patologia Orale, Dipartimento di Medicina Chirurgia e Odontoiatria, Universita` degli Studi di Milano, Milano,Italia; 2Oral Medicine Unit, UCL Eastman Dental Institute, London, UK

At a workshop coordinated by the WHO Collaborating

Centre of Oral Cancer and Precancer in the United

Kingdom, issues related to management of patients

affected by oral leukoplakia were discussed by an expert

group. The consensus views of the working group arepresented here. Although removal of a lesion still seems

to be the predominant method of treatment by the

majority of relevant health care professionals, no rand-

omized controlled trials have been undertaken to test the

hypothesis that excision either by scalpel or laser greatly

influences the potential for later malignant transforma-

tion within the oral mucosa of an affected individual.

Results of observational studies indicate that, although

surgery may have a beneficial effect, this is not likely to

reduce the risk of later recurrence nor malignant trans-

formation at the same or another site. Medical measures

that lessen the size, extent or histopathological features

of dysplasia within leukoplakia likewise presently do not

seem to be of particular promise, as relapse or later

malignant transformation can occur, and there is a risk of

adverse effects, particularly with systemic agents (which

themselves may be contra-indicated in some individuals).

While the risk of malignant transformation, and the

development of further potentially malignant disease

may theoretically be reduced by cessation of risk activ-

ities, such as tobacco usage and alcohol consumption,

there remain no good studies that demonstrate that such

measures significantly reduce such events.

J Oral Pathol Med(2008) 37: 6369

Keywords: leukoplakia, oral; pre-cancerous conditions; surgery;

evidence-based medicine

Introduction

The terminology related to potentially malignant disor-ders of the oral mucosa (PMD) were discussed by an

expert group at a workshop coordinated by the WHOCollaborating Centre for Oral Cancer and Precancer inthe United Kingdom (1). The consensus views of theworking group are presented in a series of papers. In thisreport, we review the literature on the reported evidenceon the management of oral leukoplakia, the mostcommon PMD encountered in clinical practice.

To critically assess the available literature on man-agement of leukoplakia, or even better, of a patientaffected by leukoplakia, it is of primary importance toestablish the aims of such management. As leukoplakiais essentially an asymptomatic lesion, outcomes must beconsidered in terms of recurrence of disease or trans-formation to oral squamous cell carcinoma (OSCC) at a

similar or distant site. Unfortunately, a variable pro-portion of leukoplakia undergoes malignant transfor-mation (2). A recent study based upon epidemiologicaldata of European patients, concluded that the upperlimit of the annual transformation rate of oral leuko-plakia is unlikely to exceed 1% (3).

On the basis of such data, it should be deduced thatthe first aim in the management of leukoplakia is toavoid malignant transformation and, as a consequence,it might be appropriate to consider outcomes of therapyof leukoplakia in terms of later expected OSCCincidence. Elimination or reduction of the size of thelesion (extent) cannot be considered an acceptableindicator of treatment efficacy as recurrence is commonevent (perhaps as high as 30% in the same or anotheroral mucosal site) and it cannot be excluded thatrecurring lesions represent a high risk group. In addi-tion, histopathological change (i.e. lessened or resolu-tion of dysplastic features) cannot be considered arobust and useful outcome. The predictive value, utility,and weaknesses of dysplasia scoring systems are dis-cussed in a separate report in this series (4). Even lessuseful are the numerous biomarkers proposed as indi-cator of success in leukoplakia treatment. In fact,although some of them seem to have a good predictivevalue for OSCC onset (5), none of them has been so far

Correspondence: Giovanni Lodi, Unita` di Medicina e PatologiaOrale, Dipartimento di Medicina Chirurgia e Odontoiatria, Universita`degli Studi di Milano, via Beldiletto 13, Milano 20142, Italia.Tel: +39 02 50319021, Fax: +39 02 50319041, E-mail: [email protected] for publication May 12, 2007

doi: 10.1111/j.1600-0714.2007.00575.x

J Oral Pathol Med (2008) 37: 6369

2007 The Authors. Journal compilation Blackwell Munksgaard All rights reserved

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validated as surrogate endpoint for prevention of

malignant transformation.

Surgical treatment

Although surgery is the first choice in the managementof oral leukoplakia by most relevant specialists (6, 7),the hypothesis that removing potentially malignant orallesions by different surgical techniques (scalpel, laser,and cryosurgery) can prevent the onset of oral cancer,remains unproved. To date there is only one reportedrandomized controlled trial (RCT) evaluating surgicaltreatment of leukoplakia (8). This study did not provideparticularly helpful information on the effectiveness ofsurgical excision of leukoplakia in preventing OSCC as

while comprising two active arms (CO2 and Er:YAGlaser), no control arm (no treatment) was included andthe duration of follow-up was probably too short (2496 weeks) to assess the incidence of later OSCC. Asidefrom this single RCT, all the other data come fromfollow-up studies, mostly retrospective (i.e. based onclinical files revision), describing rates of malignanttransformation in patients who underwent surgical (e.g.scalpel excision) or laser treatment of oral leukoplakia(922) (Table 1). Results from such studies are hardlycomparable because of differences in diagnostic andinclusion criteria, follow-up time intervals, patientcharacteristics, and surgical techniques employed; and

perhaps as a consequence have highly variable resultsand sometimes conflicting conclusions (18, 23). It mustbe added that the interpretation of data is often madeeven harder by the quality of the report. The retrospec-tive design of most of the surgical interventional studiescreates bias. For example, the selection of patients mayhave been determined by the site, size, nature orhistopathology of the lesion, as well as the health andwishes of the patients. In one of the few studies thatcompared the incidence of cancer in a group undergoingsurgical excision with different techniques and a groupuntreated, the authors concluded that, there was noobvious difference in the malignant transformation rate

between patients who received any surgical treatments

(5.5%, 591) and those who did not (7.8%, 451) (18). Itis noteworthy that similar conclusions were reachedabout 40 years ago by Einhorn and Wersall whoreported that, There is no evidence that the incidenceof oral carcinoma can be diminished by surgical removalof the leukoplakia (24). The same authors added, thisdoes not mean that (surgical removal) should beabandoned, mainly for histologic diagnosis. Againthese researchers were far-sighted. In fact an importantissue in discussing the role of surgical removal in themanagement of leukoplakia is the potential relevance ofexcisional biopsy as a diagnostic tool. Indeed someauthors have reported high frequencies (>10%) ofOSCC in the specimens of lesions that were excised

following an incisional biopsy that seemed to suggestthat there was no OSCC in the region of interest (21,25). Although such findings are not consistent with themajority of studies, they do suggest that even ifexcisional biopsy of leukoplakia it is not effective asan intervention of primary prevention (i.e. to preventmalignant transformation), it may have a role asintervention of secondary prevention (i.e. to detect veryearly cancer undetected by an incisional biopsy).

Among the different surgical techniques proposed forthe treatment of leukoplakia, laser surgery has probablyreceived the greatest attention, there being reports ofthis over the past 30 years1. Unfortunately, as with

other surgical techniques, most studies have majormethodological flaws and are very low in the hierarchyof evidence (Table 2).

Carbon dioxide, NdYAG, and KTP laser have beenemployed with various vaporization or excision tech-niques for the treatment of oral leukoplakia. The mainadvantages of laser therapy are the potential haemo-static effects and the potential for limited tissue con-traction and scarring post-therapy, both of which maypermit the treatment of lesions of large dimensions.

Table 1 Transformation rate in groups of patients with leukoplakia undergoing surgery

Technique No. of patientsFollow-up: mean

(range)Recurrences

or new lesionsPatients who developed

OSCC Reference

CO2 laser, V 39 (69 lesions) 42 m (2102) 3369 lesions (47.8%) 5 (20%) (9)CO2 laser, E 54 2 years 2 patients (3.7%) 0 (10)CO2 laser, E 28 5.4 years (39.5) 5 patients (17.8%) 3 (10.7%) (11)CO2 laser, V 14 29 m (1241) 8 patients (57.1%) 1 (7.1%) (12)

CO2 laser, V or E 44 lesionsa

10 m (424) 644 lesions (13.6%) 0 (13)Blade 89 patients 6.8 years (1.518.6) 1289 (13.5%) 1189 (12.35%) (14)Various 97 lesionsa Unknown but >6 m 3197 lesions (32%) 3 (higher than 4%) (15)Blade 53 Unknown but >12 m 9 patients (17.0%) 0 (16)CO2 laser, E 103 lesions

a 5.3 years (0.512) 10103 lesions (10%) 0 (17)Various 91 4 years (0.516) 5 (5.5%) (18)Cryosurgery 60 Unknown (2.54.5 years) 12 patients (20%) 4 (7%) (19)CO2 and Nd:YAG laser, V or E 55 32 m (6178) 21 patients (38.2%) 5 (9%) (20)CO2 laser, V or E 55 18 m (144) 12 patients (22%) 4 (7%) (21)CO2 laser, E 200 52 m (1219) 28282 lesions (10%) 3 (6%) (22)

E, excision; V, vaporization.aNumber of patients not available.

1Searching Pubmed using the two terms leukoplakia and laser 115records were obtained on October 2006

Treatment of oral leukoplakia

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Other favorable features of laser therapy may includereduced post-operative pain, swelling, and infection.Nevertheless, laser surgery is not the panacea ofleukoplakia therapy as treatment must always bepreceded by histopathological confirmation of thenature of the lesion, wounds may take longer to re-epithelialize, small granulomas can complicate healing(26) and histopathological confirmation of the nature ofthe excised lesion is not possible if ablation techniques

have been employed. A study comparing different lasertechniques, CO2 laser, NdYAG laser, and KTP, dem-onstrated differences in recurrence rates (34.2%, 28.9%,and 17.0%, respectively); however, only six patientswere included in the KTP group whereas the CO2 andNdYAG groups comprised 38 and 36 patients, respect-ively.(15).

Cryosurgery does not seem to be of particular benefit,recurrence rates of 2071.4% (15, 19) being reported,along with malignant transformation rates of 725%(18, 19). As mentioned previously, the only RCT onsurgical treatment of leukoplakia is a two-arm studycomparing CO2and NdYAG lasers. Unfortunately, thesmall number of patients (10 subjects) and the shortfollow-up (range 2496 weeks), do not allow any soundconclusions although the authors stated that, bothtreatment approaches seem to have limitations toachieve predictable eradication of oral leukoplakia.

Medical treatment

In the update of a Cochrane review (27), nine RCTstesting medical therapy for management of leukoplakiawere found following an extensive literature search. Thechemopreventive agents employed included local and

systemic vitamin A and retinoids, (2832), systemic betacarotene (31), lycopene (a carotenoid) (33), ketorolac (asmouthwash) (34), local bleomycin (35), and a mixture oftea used both topically and systemically (36).

Only two studies reported useful data on malignanttransformation (31, 35) and unfortunately none of thethree treatments tested (topical bleomycin, systemicvitamin A, and systemic beta carotene) were of benefitwhen compared with placebo (Fig. 1).

Data on complete resolution of the oral lesions wereavailable from all the nine studies included in the review.Two studies showed a small but significant benefit forthe systemic treatment with beta carotene (31) orlycopene (33) when compared with the controls. VitaminA or retinoids (2932) were also of some benefit.Unfortunately, the recurrence rates among those whoresponded to treatment were high (2064%) whenreported (2064%), as well as adverse effects (up to100%) (27). The current conclusion of the systematicreview is that none of the treatments investigated areeffective in preventing malignant transformation of oral

leukoplakia.

Cessation of risk activities

Although tobacco is often indicated as the principal riskfactor for leukoplakia (37), no studies on groups ofsmokers are available to assess the effect of cessation ofsuch habits upon the chance of malignant transforma-tion. However, educational programs encouragingsmoke cessation can lead to a decrease in the incidenceof leukoplakia (38) and smoking cessation may causeresolution of a fair number of leukoplakias (39).

A single study on effect of cessation of smokelesstobacco was found. In that study, a group of military

trainees stopped chewing tobacco. After 6 weeks, mostleukoplakias (97.5%) had resolved (40). As it is likelythat smokeless tobacco leukoplakia is a lesion withspecific characteristics, such results cannot be extendedto lesions associated with smoked tobacco.

Wait and seeA possible management approach might be to simplykeep a leukoplakia under strict clinical and histologicalsurveillance, with frequent clinic visits and biopsies, butwithout active intervention. In this case, the clinical aim

Table 2 Hierarchy of strength of evidence for treatment

Study design

Systematic reviews of randomized controlled trialsRandomized controlled trialNon-randomized controlled trialObservational studiesCase series

Case report

Figure 1 Medical treatment for the prevention of leukoplakia transformation [from Lodi et al. (27)].


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is to make a diagnosis of malignant transformation asearly as possible, to treat the oral cancer at a very initialstage, thus possibly providing the best possible progno-sis. An observational retrospective study by Schepmanet al. compared the incidence of OSCC in two groups ofsubjects with leukoplakia, one comprising patients whounderwent any active treatment (medical andor surgi-cal) and the other patients kept under regular clinicalfollow-up (37). As shown in Fig. 2, there was nosignificant difference in the risk of malignant transfor-mation between the two groups thus perhaps suggestingthat the natural history of leukoplakia might be inde-pendent from the treatment, and that there is asubgroup of lesions destined to malignant transforma-tion regardless of the therapy adopted. However, aspreviously mentioned, observational studies may haveserious selection bias. In this case, for example, it ispossible that lesions considered at higher risk had agreater likelihood of being actively treated, whereaslesions with a less troubling clinical appearance mayhave been more likely to be selected for higher surveil-

lance only, thus overestimating the transformation ratein treated lesions and underestimating the same variablein non-treated lesions.

Discussion and critique

Leukoplakia is considered to be the most commonpotentially malignant disorder of the oral mucosa.Nevertheless, there remains little evidence that thereis a reliable and safe method of stopping therecurrence of leukoplakias, and the potential forOSCC development.

As highlighted earlier, there remain considerable flawsin many of the studies of determining the most effective

means of treating potentially malignant disease of the oralmucosa. Previous studies did not always detail histopath-ological responses to therapy, definitions of response totherapy were not always uniform, long-term follow-upwas not detailed inany study and there was a frequent riskof bias. Additionally, it is not always possible to deter-mine the exact disease that was being investigated, asleukoplakia is a clinical manifestation of oral epithelialhyperplasia, dysplasia and malignancy, and there is a risk

that pre-treatment histopathological assessment may notbe representative of the most clinically significant disease(i.e. the most worrisome degrees of dysplasia beingpotentially underrepresented).

Surgical excision of oral leukoplakia-like lesions doesnot reduce the risk of subsequent disease (23, 41), indeedthe risk of subsequent malignant transformation may notbe lowered by surgical removal of a leukoplakia (23, 24).Nevertheless, surgical excision does allow the opportun-ity for examination to ensure all areas of dysplasia havebeen identified (usually by histopathological examina-tion) and excised. The value of histopathological exam-ination of frozen sections to ensure adequate clearance ofdisease at surgical margins [as with OSCC (42)] may notbe helpful as it will not detect areas of ploidy (if relevant) and surgeons may have to be more aggressive in theexcision of disease than they usually practice (43).Recurrence of leukoplakia following laser excision islikewise high (7.738.1%), and later malignant transfor-mationmaybe ashigh as6% (15,22), but perhaps may bereduced by use of a micromanipulator and operative

microscope as opposed to a conventional handpiece.Post-operative re-epithelialization can be slow followinglaser excision, there is the need for appropriate health andsafety safeguards and the requirement for conventionalsurgical excision of areas of histopathological interests(26). Cryotherapy is not considered to be a first linetherapy of oral leukoplakia and related disorders, byvirtue of its lack of widespread clinical availability andrisk of post-operative scarring, tissue contraction andimportantly the resultant inability to observe signs ofclinical recurrence (19, 44, 45). Hence, at the present time,no physical method of local excision of oral leukoplakiaguarantees long-term resolutionof relevant oral epithelialdisease, or the possibility of the development of OSCC.

Photodynamic therapy (PDT) is considered by somespecialists to be of future application for the manage-ment of oral leukoplakia. In principal, PDT would seemto offer the potential for localized and effective eradica-tion of areas of dysplasia by virtue of the differentialuptake of a photosensitizer, but to date there have beenfew reports of the efficacy of PDT for the treatment oforal epithelial dysplasia (OED) and leukoplakia (4649).Topical photosensitizers such as 5-ALA lessen the risk ofcutaneous photosensitization, but may not cause resolu-tion of the leukoplakia (49). To date, while PDT seemsattractive, and may have application for the palliativecare of advanced head and neck malignancy (48, 50) and

the management of early OSCC (48), there is limited datato suggest that PDT will resolve existing leukoplakias orprevent future similar or neoplastic disease.

As noted earlier, a spectrum of different systemic andtopical retinoids, and other agents, have been investi-gated in RCTs for efficacy in the treatment of potentiallymalignant disease, but there remain limited data as totheir exact efficiency, and their long-term local andsystemic consequences are largely unknown.

Blocking Epidermal Growth Factor Receptor(EGFR) related pathways via inhibition of cyclo-oxygenase (COX) 2 and EGFR tyrosine kinases isattractive, particularly in the light ofin vitroand animal

Figure 2 Follow-up of 166 patients with oral leukoplakia, of whom87 had active treatment (intervention) and 79 had not (surveillance)(P = 0.18), an event is defined as a malignant transformation [fromSchepman et al. (23)].


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studies of OSCC (51), however, the application of COX-2 inhibitors for the prevention and treatment ofleukoplakia, particularly in persons with tobacco-rela-ted risks of arteriosclerosis, would seem to be verylimited. Similarly, the use of topical non-specific COXinhibitors (e.g. ketorolac) may be limited by poorpenetration of the agent into areas of hyperkeratosis(34).

A viral basis for some leukoplakia-type lesions hasbeen suggested, as not all affected persons have thecommonly identifiable risk factors of tobacco usageandor alcohol consumption. Human papillomaviruses(HPVs), in particular high risk types 16 and 18, havebeen detected in up to 85% of examined leukoplakia-type lesions (52), although the mean prevalence of HPVcarriage in such disease is 30%. Similarly, HPV has beenvariably detected in other potentially malignant oralmucosal disease. However, the exact association of HPVwith OED still remains unclear, although perhaps aswith head and neck SCC (53, 54), a subset of patientsmay have virally associated disease amenable to specific

therapies. At present, agents such as imiquinod areavailable for the treatment of cutaneous HPV infection(55), but are not licensed for oral topical application,hence it is not known if such an approach would be oftherapeutic benefit for OED (56). Preventative strategiessuch as vaccination may be applicable, indeed whensuch vaccines do become widely available, it will bepossible to assess the real impact of HPV upon thedevelopment of OED, and whether oral leukoplakia isprevented (57, 58).

Antifungal strategies may seem attractive for thetreatment of leukoplakia as correlations between theintra-lesional presence of candida and degree of OED(59,60) and between the frequency of oral yeast and

likelihood of OED or SCC (61) have also been reported.Likewise, it is suggested that chronic hyperplastic cand-idosis (CHC) mayhave some malignant potential(62, 63).Nevertheless, although there have been suggestions thatboth topical and systemic therapies may lessen clinicalsigns of CHC (64, 65), there is no good data indicatingthat topical or systemic antifungals reliably resolveleukoplakias nor lessen the risk of malignancy in themouths of affected individuals. Similarly, although linksbetweenT. palliduminfection and OSCC risk have beenpostulated, antibacterial strategies would presently seemto have no logic for the management of oral leukoplakia.

As with other disorders because of alcohol, and

particularly tobacco, it may be possible to lessen the riskof leukoplakia (and OSCC) by cessation of tobaccousage andor alcohol consumption. However, it isestimated that it may be 1015 years before the risk ofOED lessens significantly (66). A major hindrance toeven exploring the potential benefits of cessationprograms remains the poor uptake and long-termcompliance of patients. Similarly, while dietary supple-mentation (i.e. enhanced intake of fresh fruit andvegetables) may theoretically lessen the malignantpotential of the oral epithelium (67), it may be difficultfor patients to comply with such change, particularly ifeconomically deprived.

Conclusion

Until appropriate long-term studies of effective ther-apy of well-defined disease are undertaken, it must beassumed that at the very least leukoplakias should beremoved in their entirety, patients regularly monitoredfor further relevant mucosal change, and directed toavoid the major risk factors of oral epithelial dyspla-sia, in particular tobacco usage and alcohol consump-tion. Until the question of how best to identify lesionswith OED is answered (as discussed in previousaccompanying papers in this series) it would seembest to presume that all isolated white lesions arepotentially malignant and thus treat them all similarly.The long-term specialist monitoring of patients withprevious leukoplakia (like that of oral lichen planus) isunclear, however to ensure effective utilization ofresources such monitoring should be shared by bothprimary and secondary health care providers, thisbeing optimized by appropriate education of theformer by the latter.

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