Is there any benefit in surgery for potentially malignant disorders of the oral cavity?

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1 doi: /jop (2014) 43: John Wiley & Sons A/S. Published by John Wiley & Sons Ltd wileyonlinelibrary.com/journal/jop REVIEW ARTICLE Is there any benefit in surgery for potentially malignant disorders of the oral cavity? I. Balasundaram 1, K. F. B. Payne 2, I. Al-Hadad 1, M. Alibhai 1, S. Thomas 1, R. Bhandari 1 1 Department of Oral and Maxillofacial Surgery, Royal London Hospital, London, UK; 2 Department of Oral and Maxillofacial Surgery, Kings College Hospital, London, UK Oral epithelial dysplasia grading is currently recognised as the most useful prognostic indicator for predicting conversion of potentially malignant disorders of the oral cavity to squamous cell carcinoma. It is also used as a basis for deciding management options. However, the diagnosis of oral epithelial dysplasia is subjective and thus unreliable. Surgery is currently recommended for removal of high-risk lesions; however, the evidence for its success is lacking, and in some cases, there have been reports of increased recurrence of malignancy following surgical excision. Molecular and genetic markers have been identified and show promising results in identifying which potential malignant disorders are at risk of malignant transformation. The current evidence available for prognosis of potential malignant disorders and its treatment is based on observational and retrospective data. No randomised control trials have been conducted to date to assess the efficacy of surgery in oral epithelial dysplasia. Until good quality evidence is available from well-designed randomised control trials, experts still recommend the surgical removal of potential malignant disorders which are regarded as high risk. (2014) 43: Keywords: leukoplakia; oral epithelial dysplasia; potentially malignant disorder; surgery aims to identify whether current evidence advocates surgical intervention in the management of oral OED and other PMDs of the oral cavity. Articles were identified on PubMed using the search terms oral, epithelial, dysplasia, surgery with further articles identified from cross-referencing. Classifications systems for oral epithelial dysplasia Oral epithelial dysplasia demonstrates distinct histological differences from normal tissue while not meeting diagnostic requirements for carcinoma. Most pathologists grade OED according to a combination of architectural and cytological changes, shown in Table 1 (2). There are several classification systems for oral epithelial dysplasia described in the literature: oral epithelial dysplasia, squamous oral intraepithelial neoplasia and the Ljubljana classification (Table 2) (3). Most commonly, the World Health Organisation (WHO) classical oral system is used and dysplasia is graded into mild, moderate or severe. In mild dysplasia, changes are seen in the lower third of the epithelium with minimal cytological atypia. In moderate dysplasia, the middle third Table 1 Microscopic features associated with oral epithelial dysplasia [adapted from Barnes et al. (2)] Introduction Currently, the management of oral epithelial dysplasia (OED) and other potentially malignant disorders (PMD) of the oral cavity is debated. Because the quality of life and survival from head and neck cancer remains poor (1), it is important to identify and treat PMDs of the oral cavity to prevent malignant transformation or recurrence. This review Correspondence: Indran Balasundaram, Department of Oral and Maxillofacial Surgery, Royal London Hospital, Flat 26, 100 Westminster Bridge Road, London, SE1 7XA, UK. Tel: , indranb@hotmail.com Accepted for publication May 2, 2013 Cellular changes Abnormal variation in nuclear size (anisonucleosis) Abnormal variation in cell size (anisocytosis) Increased nuclear/cytoplasmic ratio Enlarged nuclei and cells Hyperchromatic nuclei Increased mitotic figures Abnormal mitotic figures (abnormal in shape or location) Nuclear and cellular pleomorphism Increased number and size of nucleoli Architectural changes Loss of polarity Disordered maturation from basal to squamous cells Includes top-to-bottom change of carcinoma in situ Increased cellular density Basal cell hyperplasia Dyskeratosis (premature keratinisation and keratin pearls deep in epithelium) Bulbous drop-shaped rete pegs Secondary extensions (nodules) on rete tips

2 240 Table 2 Classification schemes for histopathological levels of H&N epithelial dysplasia [adapted from Warnakulasuriya et al. (3)] Classic oral system (WHO, 2005)(3) Oral intraepithelial neoplasia (OIN) System Ljubljana system (for laryngeal keratosis) of the epithelium is involved demonstrating mild atypia. In severe dysplasia, more than two-thirds of the epithelium is involved demonstrating architectural disturbance and cellular atypia, or architectural disturbance without cellular atypia extending to the middle third warrants this diagnosis. Carcinoma in situ is diagnosed when architectural abnormalities and pronounced cellular atypia involve the whole epithelium, and oral squamous cell carcinoma (OSCC) is diagnosed when epithelial nest cells have invaded the underlying lamina propria. It is generally regarded that the more severe the dysplasia, the greater the chance the lesion will progress to malignancy (4). Despite this, non-dysplastic lesions can also demonstrate malignant transformation and severe dysplastic lesions can regress (5). The classification/grading systems of epithelial dysplasia should serve as a method of predicting risk of malignant transformation and hence management options. However, no single classification system has been found to be ideal. Grading OED is subjective and has been shown not to be reproducible (6 8). Clinical presentation of underlying oral epithelial dysplasia Classic laryngeal system No dysplasia n/a Simple hyperplasia Laryngeal keratosis Mild dysplasia OIN 1 Basal/parabasal Hyperplasia hyperplasia Moderate dysplasia OIN 2 Atypical hyperplasia Keratosis with dysplasia Severe dysplasia OIN 3 Carcinoma in situ OIN 3 Carcinoma in situ Carcinoma in situ Clinically, OED can present as a white (leukoplakia), red (erythroplakia) or a mixture of white and red (erythroleukoplakia) mucosal lesion, but it can also be found in normalappearing mucosa. Both leukoplakia and erythroplakia are noted as PMDs. The definitions of leukoplakia have varied over the last few decades and are shown in Table 3 (9). Clinicians also recognise that this lesion should be nonwipeable to differentiate leukoplakia from pseudomembranous candidiasis. Erythroplakia is defined similarly to leukoplakia, except as a red patch. It should be noted that leukoplakia is a clinical and not a histological diagnosis. Histologically, it can show atrophy or hyperplasia, and it may or may not show evidence of dysplasia (10). The converse can be said for OED, which is not a clinical diagnosis but a histological one. Prevalence of leukoplakia has been estimated between 1.49% and 4.27% and has been noted as one of the most common PMDs of the oral cavity (11). The rate of malignant transformation of leukoplakia into SCC varies from 0 to 20% in 1 20 years and that the upper limit of annual transformation is unlikely to exceed 1% (12 15). Non-homogenous leukoplakias may show a higher risk of malignant transformation when compared with homogenous lesions. Furthermore, those lesions with signs of dysplasia have an approximately 10% higher risk of transformation (16). Table 4 below shows a list of features which have been reported to increase the risk of malignant transformation in leukoplakia where the presence of OED is regarded as the most important factor (17). Preventing malignant transformation is important as the prognosis of OSCC is poor with a 5-year survival rate of 30 40% (1). Because the 5-year survival rate is directly related to the stage of malignancy at the time of diagnosis, prevention and early detection are vital to decrease the incidence and improve the survival odds of individuals who develop the disease (18). Treatment options Non-surgical treatment options for oral lesions with evidence of epithelial dysplasia include regular surveillance, reducing risk factors such as smoking and alcohol, and drug therapy, for example, retinoids and antimycotics. Surgical treatment methods include laser, cryosurgery or complete excision. In cases of no dysplasia to mild dysplasia, the decision to observe vs. definitively treat the lesion may be influenced by the site of origin and clinical subtype of leukoplakia. Lesions that exhibit carcinoma in situ or early invasive OSCC warrant excision with margins, and there is little dispute in the literature regarding this. For lesions that demonstrate moderate to severe dysplasia, and mild dysplasia in high-risk sites, treatment options are variable and Table 3 Definitions for leukoplakia [adapted from Warnakulasuriya et al. (9)] Working group WHO (1978) First International Conference on oral leukoplakia. Malmo, Sweden (1984) International Symposium, U ppsala, Sweden (1996) WHO (1997) WHO (2005) World Workshop on Oral Medicine (2007) Definition A white patch or plaque that cannot be characterised clinically or pathologically as any other disease A white patch or plaque that cannot be characterised clinically or pathologically as any other disease and is not associated with any physical or chemical causative agent except use of tobacco A predominantly white lesion of the oral mucosa that cannot be characterised as any other definable disease A predominantly white lesion of the oral mucosa that cannot be characterised as any other definable lesion Not defined no distinction is made from other white patches Leukoplakia should be used to recognise white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk of cancer

3 Table 4 Reported risk factors for statistical significance for malignant transformation of leukoplakia, listed in a random order [adapted from van der Waal (17)] Risk factors for the malignant transformation of leukoplakia Female gender Long duration of leukoplakia Leukoplakia in non-smokers Location on the tongue and/or floor of the mouth Size >200 mm 2 Non-homogeneous type Presence of epithelial dysplasia DNA aneuploidy there seems to be a lack of consensus regarding the definitive treatment modality (18). Surgical excision using a scalpel may or may not remove a clinically involved margin. This can lead to high recurrence rates, which has been described in the literature. Large and widespread lesions that are excised can cause significant morbidity, scarring and damage to surrounding structures which may require free tissue transfer to reconstruct the defect. Cryosurgery ablates tissues by freezing them. However, this method lacks depth control and provides no tissue specimen for further histological diagnosis. This is also a problem with CO 2 lasers which evaporates the tissue leaving no sample for histology. Using a laser for excision is seen as advantageous over the traditional scalpel method. Here, healing occurs by secondary intention, and there is less tissue distortion as well as achieving haemostasis. The disadvantage of laser is that the margins are cauterised therefore preventing examination of spread of OED or malignancy. Evidence for surgical vs. non-surgical intervention A Cochrane review published in 2006 (which reviewed 25 randomised control trials (RCTs) but only 9 were included after exclusion) could not identify any RCTs assessing the use of surgery in leukoplakia. They found some evidence for vitamin A, retinoids, beta carotene and lycopene, which may completely resolve the oral lesions or promote histological improvement (16). However, these results were based on a small number of patients. The conclusion of this systematic review was that none of the treatments investigated are effective in preventing malignant transformation of oral leukoplakia. The World Workshop on Oral Medicine IV met in 2005 and a group of experts reviewed the literature regarding the management of OED from 1966 till 2006 (19). The article published by the expert group concluded Because of the lack of RCTs, no evidence-based recommendations can be provided for specific surgical (including lasers and electrodissection) interventions of dysplastic oral lesions. No evidence-based therapeutic recommendations can be provided for nonsurgical (medical) interventions either with the possible exception for systemic administration of lycopene. Lodi et al. (20) identified a number of studies (13 in total) looking at the use of ND YAG/Er YAG laser, CO 2 laser, cryotherapy and surgical excision in treating leukoplakia. Only one RCT was identified comparing the CO 2 and Er/ YAG laser, with a follow-up of weeks and a cohort of 10 patients. This RCT reported complete or partial remission in all patients during follow-up and favoured CO 2 over Er/YAG laser. However, the authors of this RCT themselves state both treatment approaches seem to have limitations to achieve predictable eradication of oral leukoplakia (21). The remaining studies reported in Lodi s paper were retrospective, and the results are not comparable due to differences of inclusion criteria, follow-up times, patient characteristics and treatment options, and therefore, the results will inevitably be highly variable and in some cases were contradictory. From our literature search, 2 retrospective studies were identified which specifically addressed the issue of the outcomes of patients diagnosed with OED who were treated either with surgery or not, and these are discussed in further detail below. Arduino et al. (22) published a retrospective review of 207 patients diagnosed histologically with OED between 1991 and Patients had a minimum of 12 months follow-up and were excluded if there were clinical or histological signs of lichen planus or SCC. Patients were also excluded if survival status could not be confirmed or recall checks could not be performed. Histopathological features were graded as mild, moderate or severe and treatment was classified as follows: surgery (scalpel, laser and cryotherapy) and no treatment. Patients with moderate or severe dysplasia involving the lateral or ventral surface of the tongue and if medically fit were strongly recommended for surgery. A few patients within the above category opted not to have surgery for personal reasons. Patients were encouraged to stop smoking, and evidence of candida was treated. The evolution of disease was detailed as healing, recurrence or oncological event. One hundred thirty three patients had surgical treatment, with a 5-mm margin of normal tissue. Five patients with small lesions were treated with cryotherapy. Biopsies were taken in case of recurrence or further oncological event. Only 40% of patients achieved cessation of risk factor associated behaviour. Of the patients who did not have surgical treatment, 55 had mild OED, 13 moderate OED and six had severe OED. Those with speckled areas or severe dysplasia were reviewed every 3 months and all others reviewed every 6 months. During the follow-up period, 40% of the lesions disappeared, 27% remained stable and 34% demonstrated a new dysplastic event after treatment. No differences were found between treated and untreated groups. No difference was found between different degrees of OED, types of lesions and site. The only significant difference was found in patients who continued to expose themselves to risk factors and as a result were more likely to have recurrence (OR = 2.43). Nine men and six women developed SCC after a median of 30 months. Gender, histology and treatment group were not significantly greater or different in the malignant group. However, age >70 (OR = 2.67) and speckled lesions (OR = 2.7) showed an increase risk of malignant transformation. The authors did not find an association between the severity of dysplasia and therapeutic failure. However, 241

4 242 alcohol and tobacco seemed to be independent risk factors, and therefore, it is suggested recommendations to reduce alcohol consumption and smoking could potentially reduce recurrences. As with other disorders, it is estimated that it may take years before this risk lessens significantly (23). The authors note due to the subjectivity of grading, it is difficult to assess transformation rates of OED to SCC. However, in this series, grading had no value in predicting malignant change. Although surgery is generally the first choice of management in potentially malignant oral lesions, the evidence from this study does not demonstrate any benefit in preventing the onset of oral cancer or preventing recurrences. This study was not randomised, and therefore, the groups are not comparable, notably those who were offered surgery were deemed to have high risk lesions in high risk sites, which significantly adds bias to the results. Holmstrup et al. (24) published a retrospective review documenting the outcome of 269 lesions of OED in 236 patients over the time period % of the lesions were homogenous lesions, 25% non-homogenous leukoplakias and 5% erythroplakia. Patients with evidence of OED on the ventral and/or lateral surface of the tongue as well as the sublingual region were recommended for surgical removal. Other patients were seen for regular follow-up and examination. In total, 94 lesions were surgically removed in 89 patients (41% homogenous, 49% nonhomogenous leukoplakia and 9% erythroplakia). 73% of the lesions were associated with tobacco. 175 lesions in 147 patients received no surgical treatment (85% homogenous, 11% non-homogenous leukoplakias and 3% erythroplakias). 81% of these lesions were associated with tobacco with 12% displaying OED. 37% of all lesions were not biopsied, either due to patient refusal or were deemed low risk. The only variables noted to be of any significance in malignant transformation were non-homogenous leukoplakia type lesions (Odds ratio of 7) and where size was >200 mm 2 (odds ration 5.4). The other variables studied, including histology (carcinoma in situ vs dysplasia vs no dysplasia), surgery vs. no surgery, well-demarcated borders vs. diffuse demarcation and smokers vs. non-smokers, did not demonstrate a statistical significance in increased risk of malignant transformation. Most important to note was that surgery did not prevent malignant development which is consistent with other studies (25 27). 13% of the surgically treated lesions developed cancer in comparison with only 4% in the non-surgical group. Also of note was that histological features (dysplasia vs no dysplasia) had no correlation with predicting malignant outcome. The authors felt it was relevant to compare degree of dysplasia with no dysplasia as they realise the diagnosis of dysplasia can be subjective. However, the degree of epithelial dysplasia also did not predict malignant outcome % of lesions which displayed slight OED, in both the surgical and nonsurgical treated groups, developed carcinoma. This bears relevance when comparing with previous studies that have regarded this degree of OED as harmless (28, 29). Similar comments can be made about 11% of surgically treated lesions without OED and 5% of non-biopsied leukoplakias which developed malignancy. Regarding these findings, the authors do note that the initial biopsy result is an important factor in determining management, and in some cases, biopsies were performed years before the end of follow-up. In that time, histological features may have progressed even though they may not have been noted clinically. Also it is questionable whether the biopsy is representative of the whole lesion. The authors recognised that the lateral/ventral border of the tongue and the floor of mouth were seen as at risk sites, and therefore, these patients were recommended for surgery. However, statistical analysis did not demonstrate this. Another finding the authors noted as remarkable was that 20% of surgically treated non-homogenous leukoplakias developed cancer and the frequency of malignant development in the same lesions without surgical intervention was 15%, therefore questioning whether surgical treatment actually acts as a cancer promoter. Experimental work by Maeda et al. on hamsters has noted an increased incidence of cancer after surgical excisions of tongue mucosa treated with carcinogens (30). Another explanation for the poor results with surgery may be due to the multiclonal origin of the affected areas seen in field cancerisation which considers that there are cancer-stigmatised cells outside the removed lesion (31). This study was retrospective and the treatment groups were not randomised and probably therefore not quite comparable. Discussion Holmstrup has stated that one of the most important problems in oral medicine is the way we handle premalignant lesions. and how to prevent malignant development of the premalignant lesions? (32) As with other PMDs occurring elsewhere in the body, it was assumed that removing pre-malignant lesions would free the patients from the risk of cancer in the affected area. However, as discussed in this article, this assumption cannot be made with PMDs of the oral cavity. Despite surgical removal, recurrences have still been reported even at a higher rate than if the lesion was observed. Unfortunately, the majority of evidence is based on observational and retrospective data, as yet no good quality RCTs are available. For this reason, there are no universally agreed guidelines for the treatment of oral PMDs. The issue is further complicated by the fact that 5 10% of leukoplakias contain carcinoma which was not initially noted on diagnostic biopsy but only afterwards on surgical excision (33). Holmstrup addressed whether biopsies of pre-malignant lesions taken by experienced oral surgeons were representative of the whole lesion (34). In a sample of 101 lesions, when comparing degree of dysplasia in the biopsies and whole lesion, they found there was concurrent diagnosis in 49% of lesions and in 79% after inclusion of lesions with one degree up or down in the scale of dysplasia and carcinoma in situ. Under diagnosis of the biopsy was made in 35% of lesions, and over diagnosis was made in 17%. More importantly, they noted that carcinoma was present in 8% of lesions, where biopsies had shown no, slight or moderate dysplasia. On the other hand, lesions in which the biopsies showed severe dysplasia or carcinoma in situ never revealed a carcinoma in the total lesion. Therefore, should we be removing all lesions surgically to ensure correct diagnosis as well as treatment? Over

5 Table 5 Potential molecular markers for progression of oral epithelial dysplasia to carcinoma [adapted from Brennan et al. (19)] 243 Mechanism Microarray technology Loss of heterozygosity Apoptosis and cell cycle alterations Aberrant DNA expression Matrix metalloproteinases Vascular endothelial growth factor Cytokeratins Integrins Cell surface glycoproteins Granulocyte colonystimulating factor receptor Growth factor receptors Association with dysplasia Numerous inflammatory-related genes of the arachidonic acid metabolism pathway have altered expression. The presence of invasion-related genes may be useful in predicting tumour progression Loss of heterozygosity (LOH) at 3p and/or 9p increased the risk of progression of dysplasia to squamous cell carcinoma (SCC); LOH on additional chromosome arm (i.e. 4q, 8p, 11q and 17p) demonstrates even higher risk. LOH at 9p21 commonly occurs in dysplasia. Apoptosis appears in the keratinised layer in normal epithelium and benign hyperkeratosis. p53 protein and other markers of apoptosis appear in basal and parabasal layers of dysplastic lesions that progressed to SCC. Apoptosis appears to decrease with more severe dysplasia and SCC. While some studies found an association with DNA ploidy and dysplasia grade, others have found no such relationship. Matrix metalloproteinases (MMP)-1 and Matrix metalloproteinases (MMP)-9 were more commonly expressed in dysplastic tissue that progressed to SCC. EMMPRIN expression was found in oral dysplasia cell lines and dysplastic lesions Concomitant expression of vascular endothelial growth factor and of MMP-11 was more common in progressing dysplastic tissue. Cytokeratin-4 (K4), K13, transglutaminase 3 (TG-3) were suppressed and expression of K14 and K17 was elevated in SCC and severe dysplasia. K4 and K13 were detectable in moderate dysplasia, but not SCC. Integrin was associated with malignant transformation of dysplastic oral leukoplakias, but is also expressed in non-dysplastic conditions such as lichen planus. Loss of expression of isoform CD44v7-8 in dysplasia may be related to poorer prognosis. Expression elevated in dysplasia and SCC vs. normal and hyperplastic tissue. Epidermal growth factor receptor shows a linear increase in intensity of staining, suggesting an increase in dysregulation of epithelial cell proliferation with increasing degrees of dysplasia 40 years ago, Einhorn et al. found that there was no evidence that the incidence of oral cancer can be diminished with the surgical removal of leukoplakia (25). Einhorn went on to say that surgical removal still had a role, as excisional biopsy is still required to provide a histological sample. Even if there is not clear evidence for the role of surgery in preventing malignant transformation, there may be a role to detect early cancer which was initially undetected by incisional biopsy. Many articles discussed in this article have deduced the same conclusion. The grade of epithelial dysplasia is one of the most important factors used to decide the treatment of oral PMDs. However, the diagnosis is subjective and not all lesions exhibiting dysplasia become malignant and the converse is true in which malignancy can develop from lesions where there is no evidence of dysplasia. There is a need to improve histological assessment of OED or develop additional methods of predicting the malignant potential of PMD. Determining whether a dysplastic lesion will develop into cancer rests in the understanding the pathophysiology of disease progression and identifying predictive molecular and genetic markers indicative of risk. Mehanna et al. and Brennan et al. have reviewed the literature regarding the potential use of these markers in predicting the risk of malignant transformation (19, 35, 36). Despite some markers showing predictive ability, none of the markers has demonstrated prognostic prediction for OSCC which is more reliable than dysplasia, and none have been validated in independent prospective studies (Table 5) (19). Conclusion Currently, no suitable method other than the histological grading of OED has been developed for routine clinical use. While research into other areas continues, grading OED will continue to influence prognostic and treatment options. Lodi and Van der Waal both agree that until there is clear evidence for therapies in leukoplakia, all lesions should be removed in their entirety and patients monitored for mucosal changes. Patients should also be advised to reduce alcohol and tobacco consumption, which are known risk factors for OED. Until we have robust evidence detailing the best method of identifying oral mucosal lesions at risk of developing malignancy, it is sensible to assume that all potentially malignant lesions should be treated by surgical removal. Primarily for diagnostic purposes, 5 10% of lesions may contain carcinomas, which are not revealed by clinical examination or biopsy. However, with growing evidence that surgical removal, in some cases, may be associated with future recurrence and malignant development, careful follow-up examination after surgery continues to be mandatory (16, 17). Holmstrup also states that previously [we] were convinced that removal of premalignant lesions would eliminate or at least reduce the risk of malignant development, randomized trials might be considered unethical. Such studies are now to be considered urgent and highly ethical. It is unethical to continue without knowing what we are doing to our patients (32). References 1. Scully C, Porter S. ABC of oral health. 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