ORIGINAL ARTICLE TREATMENT AND FOLLOW-UP OF ORAL DYSPLASIA A SYSTEMATIC REVIEW AND META-ANALYSIS

ORIGINAL ARTICLE TREATMENT AND FOLLOW-UP OF ORAL DYSPLASIA A SYSTEMATIC REVIEW AND META-ANALYSIS Hisham M. Mehanna, MBChB, FRCS, 1 Tim Rattay, MBChB, MRCS, 1 Joel Smith, MBChB, MRCS, 1 Christopher C. McConkey, MSc 2 1 Department of Head and Neck Surgery, Institute of Head and Neck Studies and Education, Department of Head and Neck Surgery, University Hospitals Coventry and Warwickshire, Coventry, United Kingdom. E-mail: hisham.mehanna@uhcw.nhs.uk 2 Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, United Kingdom Accepted 18 February 2009 Published online 19 May 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.21131 Abstract: Background. The aim of this study was to inform an evidence-based management policy for oral dysplastic lesions. Methods. Systematic review was performed with metaanalysis. Studies reporting follow-up of patients with histologically confirmed oral dysplasia were included. Outcome measures included malignant transformation rate (MTR) and time to malignant transformation (TMT). Subgroup analysis was performed by histologic grade, clinical risk factors, and treatment modality. Heterogeneity was assessed. Results. Fourteen nonrandomized studies, reporting on 992 patients, were included. There was considerable heterogeneity between studies: mean overall MTR ¼ 12.1% (confidence interval: 8.1%, 17.9%) and mean TMT ¼ 4.3 years. Histologic grade significantly affected mean MTR (p <.008). Lesions that were not excised demonstrated considerably higher MTR than those that were excised (p ¼.003). Conclusions. Oral dysplasia showed a significant rate of transformation to cancer, which was related to grade and was decreased significantly but not eliminated by excision. Correspondence to: H. M. Mehanna This study was presented at the American Head & Neck Society Annual Meeting, San Francisco, USA, July 23, 2008, and British Association of Head and Neck Oncologists Annual Meeting, London, United Kingdom, April 25, 2008 (poster). VC 2009 Wiley Periodicals, Inc. This suggested the need for excision and continued surveillance. VC 2009 Wiley Periodicals, Inc. Head Neck 31: 1600 1609, 2009 Keywords: dysplasia; leukoplakia; oral lesion; malignancy; follow-up Oral dysplasia is a relatively common premalignant condition, which affects approximately 2.5 to 5 per 1000 of population. It is usually seen by general medical and dental practitioners in the form of leukoplakia (a white patch that does not rub off), which affects 1% to 2.5% of the population at any one time. 1 Oral dysplasia can only be diagnosed histologically. In oral dysplasia, cells of the normal oral epithelium are replaced by cells showing immature or inappropriate differentiation with a resemblance to cells usually seen in malignancy. 2 The importance of oral dysplasia lies in that a proportion of these lesions can progress to cancer. However, reports on the risk of progression to cancer vary considerably from 6% to 36%. 3 At present, the only effective treatment is surgical excision, and there are no effective 1600 Treatment and Follow-Up of Oral Dysplasia HEAD & NECK DOI 10.1002/hed December 2009

medical treatments. 4 Even surgical excision carries a high risk of recurrence (up to 35%). 5 Furthermore, resection of large lesions can cause significant morbidity and may sometimes require extensive reconstructive techniques. As a result of these controversies, there is currently no consensus over the treatment and follow-up required for patients with oral dysplasia. Management strategies vary from incisional biopsy aiming to exclude cancer to complete excision with an adequate margin. Reported follow-up strategies vary from immediate discharge to life-time follow-up. 6 To develop an evidence-based management and surveillance policy for oral dysplasia, we undertook a systematic review and meta-analysis of observational cohort and case-controlled studies to assess the risk of and interval to progression to cancer in patients diagnosed with oral dysplasia. We also examined the effects that histologic grade, clinical risk factors, and treatment strategies may have on this. PATIENTS AND METHODS Search Strategy. In accord with the meta-analysis of observational studies in epidemiology (MOOSE) guidelines, the investigators searched Medline (1966 to June 2008), Embase (1980 to June 2008), and Cochrane databases (CENTRAL, Cochrane Library, 1995 to June 2008). The last search was performed on June 4, 2008. Our core search terms were oral and dysplasia, mouth and dysplasia. Each of the searches were then combined with each of the following terms: progression, follow-up, treatment, cohort, natural history, and recurrence (Table 1). Reference lists of obtained studies, personal reference lists, and existing reviews were also searched manually. Selection Criteria. To be included in the review, studies had to report on patients with a histologically confirmed diagnosis of oral dysplasia. They also had to study at least one of the outcome measures and one intervention method or clinical risk factor. In studies on oral lesions which contained a defined subset of patients with oral dysplasia, this subset but not all patients with oral lesions were included in the meta-analysis. Observational studies were included in the review because there was a paucity of randomized controlled trials with adequate follow-up. For multiple publications Table 1. Description of search strategy. No. Search term 1 Dysplasia and oral 2 Dysplasia and mouth 3 1 or 2 4 3 and progression 5 3 and follow-up 6 3 and treatment 7 3 and cohort 8 3 and natural history 9 3 and recurrence for the same patient group, the data for the longest follow-up period were used. When an abstract was published but no full study was found, it was agreed that the authors would be contacted, but no such instances were identified from the search. Studies that reported on patients with oral leukoplakia without histologically confirmed diagnosis of dysplasia were excluded. Cross-sectional studies of the prevalence of oral dysplasia were also excluded. Data from studies in which patients with dysplasia were not reported separately or could not be extracted from the provided data were excluded. Patients with synchronous cancer at or identified within 3 months of the time of diagnosis of dysplasia were also excluded from the meta-analysis. Studies with less than 1 year follow-up were also excluded. Outcome Measures. The following outcome measures were extracted from the studies, as they were clinically relevant: the rate of malignant transformation to oral cancer and the time interval or duration to malignant transformation. Where available, data were subclassified by histologic grade of the lesion (mild, moderate, severe dysplasia, or carcinoma in-situ [CIS]) and by management strategy (surgical excision or incisional biopsy). The relative risks of malignant transformation for proven or potential clinical risk factors of progression gender, site of lesion, continuation of smoking, and alcohol intake were also extracted. Data Abstraction. Eligibility of the studies obtained from the search was determined independently from the abstracts by two reviewers (T.R., J.S.) blinded to each other s selections. Both reviewers underwent a training period in which 10 studies were assessed together with the lead author (H.M.). If a citation was deemed Treatment and Follow-Up of Oral Dysplasia HEAD & NECK DOI 10.1002/hed December 2009 1601

eligible by at least one reviewer, the article was subjected to review. Data were then extracted from the studies into a Microsoft Excel spreadsheet. Quality and Confounding Assessment. As there is no validated tool for assessing quality in systematic reviews of observational studies, quality criteria were agreed upon a priori, adapted from the levels of evidence for prognostic studies, 7 and adapted from Greenhalgh, 8 Khan et al, 9 and Laupacis et al. 10 Included in the criteria were attempts to address confounding factors within individual studies, length and rate of follow-up achieved, and blinding of assessment of outcome. The quality of the studies was assessed independently by two reviewers (T.R., J.S.). When there was disagreement, a third reviewer (H.M.) was consulted. Statistical Analysis. Outcome data were abstracted independently by a researcher (T.R.) and a statistician (C.M.) and checked by a third reviewer (H.M.). A funnel plot was generated showing individual MTRs in each study by study size. In this plot, the rates are variance-stabilized using the arc-sine square-root transformation because most were below 20%. Heterogeneity was assessed graphically in the forest plot and the exact binomial confidence intervals (CIs) were calculated. Where sufficient data existed, heterogeneity was studied in the statistical model. Transformation rates were modeled by applying a random effects logistic regression model that assumed a fixed effect of the underlying mean log-odds of transformation rate with a random study effect. This allowed estimates of the underlying mean and of the effect of covariates such as dysplasia grade and clinical risk factors. When analyzing effects of dysplasia grade, the mild and moderate subgroups were almagamated, as were severe dysplasia and CIS. This was done because it is widely acknowledged that histological grading of oral dysplasia shows significant intraobserver and interobserver variability, especially for the two diagnoses in each group. 11 RESULTS Description of Studies. The search strategy produced 2837 articles in total, of which 28 were deemed eligible and subjected to full review (Figure 1). After applying the selection criteria, eight cross-sectional studies and four observational cohort studies on oral lesions without histologically confirmed dysplasia were excluded. 12 15 There were no randomized-controlled trials or case-control studies. After exclusion of two studies FIGURE 1. Flowchart of search results. [Color figure can be viewed in the online issue, which is available at www.interscience. wiley.com.] 1602 Treatment and Follow-Up of Oral Dysplasia HEAD & NECK DOI 10.1002/hed December 2009

due to duplication of data, 16,17 14 prospective and retrospective studies were identified (Figure 1). In total, these reported on 992 patients who satisfied our inclusion criteria (Table 2). Mean or median age of the study population ranged from 47.5 to 60.8 years and was given in 7 studies. In the absence of access to individual patient data, it is important to note that these averages were derived from averages given for all patients in those studies which reported on all oral leukoplakia lesions and not just from patients with confirmed dysplasia. Median or mean follow-up ranged from 1.5 to 10 years and was stated in all but 1 study. Minimum follow-up, reported in 7 studies, is short, ranging between 6 and 12 months. Malignant transformation rate (MTR) was reported in all studies. Subgroup analysis by histologic grade was reported by 9 studies. Seven studies reported time interval to malignant transformation (TMR). Surgical treatment of dysplastic lesions by excision was specified in only 5 of 14 studies. The remaining 9 studies reported on biopsy-confirmed lesions without surgical excision. The association of malignant progression with clinical risk factors was reported in 4 studies. Quality Assessment of Studies. Three studies were population based. There were 2 prospective studies from India (level 1 evidence), 30,32 and 1 retrospective study from Northern Ireland (level 2). 21 The remainder of studies were single-institution case series from Eastern Asia, North America, and Western Europe (level 4). They used pathology slides, medical, or questionnaires sent to medical and dental practitioners to collate data. The results of the quality assessment of the studies are summarized in Table 3. Malignant Transformation and Heterogeneity of Studies. The pooled estimate for the mean MTR for all studies is 12.1% (CI: 8.1%, 17.9%), with a wide variation between studies (0% 36.4%). The rate is little affected by the mean follow-up time of the study (p ¼.26; Figure 2). To assess possible bias in the studies and examine heterogeneity, a funnel plot is shown (Figure 3). In this plot, the studies individual MTRs are variance-stabilized using the arc-sine square-root transformation because most were below 20%. The meta-analysis shows a degree of heterogeneity between studies when comparing Table 2. Description of studies included in the meta-analysis. Nonsurgically treated patients Surgical excision patients Total dysplasia patients Mean or median age, y Min. follow-up, Mean follow-up, y y Date of enrollment Methodology and setting Study Country Hsue et al 18 Taiwan Prospective hospital 1991 2001 3.6 NR 47.5 166 166 0 Holmstrup et al 19 Denmark Retrospective hospital 1977 1997 6.0 1.0 60.8 88 67 21 Saito et al 20 Japan Retrospective hospital 1976 1997 4.0 0.6 54.0 91 50 41 Cowan et al 21 Northern Ireland Retrospective population 1975 1994 NR NR NR 158 0 158 Lee et al 22 USA Prospective hospital 1988 1998 7.0 NR NR 70 0 70 Schepman et al 23 The Netherlands Retrospective hospital 1973 1997 2.5 0.5 57.0 55 0 55 Lumerman et al 24 USA Retrospective pathology laboratory 1974 1982 1.5 0.5 59.3 44 0 44 Hogewind et al 25 The Netherlands Retrospective hospital 1969 1984 2.5 1.0 NR 13 13 0 Lind 26 Norway Retrospective hospital 1970 1980 9.3 NR 57.7 47 0 47 Silverman et al 27 USA Prospective hospital <1968? 7.2 0.5 54.0 22 0 22 Gupta et al 28 India Prospective population 1966? 8.5 NR NR 90 0 90 Banoczy and Csiba 29 Hungary Retrospective hospital Not clear 6.3 NR NR 68 45 23 Silverman et al 30 India Prospective population 1967 1971 2.0 NR >35 35 0 35 Mincer et al 31 USA Prospective hospital 1963 1971 8.0 1.0 NR 45 0 45 All studies 992 341 651 Abbreviations: min, minimum; NR, not reported. Treatment and Follow-Up of Oral Dysplasia HEAD & NECK DOI 10.1002/hed December 2009 1603

Study* Methodology and setting Hsue et al 18 Prospective hospital Holmstrup Retrospective et al 19 hospital Saito et al 20 Retrospective hospital Cowan et al 21 Retrospective population Lee et al 22 Prospective hospital Schepman Retrospective et al 23 hospital Lumerman Retrospective et al 24 pathology laboratory Hogewind Retrospective et al 25 hospital Lind 26 Retrospective hospital Silverman Prospective et al 27 hospital Gupta et al 28 Prospective population Table 3. Quality assessment of studies included in review. Level of evidence Assessment of exposure (dysplasia) Sampling method bias Cohort characteristics Method of outcome assessment (cancer) Blinding of outcome assessment Adequacy of follow-up rate >80% Comments 4 Pathology 4 Medical 4 Medical 2 Pathology slides Yes All patients smoked and chewed betel; cancer within 6 months excluded Yes Concurrent cancer excluded; all smokers encouraged to quit Yes Nonsurgical treatments included cryotherapy and laser No Concurrent cancer excluded; slides were reviewed and reclassified if necessary 4 Biopsy Yes All patients received high-dose isotretinoin followed by low-dose isotretinoin versus beta-carotene maintenance 4 Pathology Yes Concurrent and previous malignancy excluded 4 Biopsy Yes Slides were reviewed and reclassified if necessary 4 Medical 4 Pathology Medical No Yes Data set checked against national cancer registry to allow for drop-outs Medical No No Surgical versus non-surgical treatment was not randomized Medical No No Surgical versus nonsurgical treatment was not randomized Medical No Yes Data for all malignant transformers available; 7 of 24 transformed in 1mohence excluded Biopsy No Yes Sample includes patients with hyperplastic lesions in high-risk sites Medical No No Not subdivided by grade of dysplasia Questionnaire administered to dental practitioners No No Only about 25% response rate to follow-up questionnaire Yes Concurrent cancer excluded Medical No No Some lesions treated by cryosurgery Yes Concurrent cancer excluded Medical No Yes Data set checked 4 Biopsy Yes Lesions > 1 cm size, persistent for > 6 months, concurrent cancer excluded 1 Biopsy No Random sample from villagers in 5 Indian districts, varying Biopsy No Yes against national cancer registry to allow for drop-outs Biopsy No Yes Ten-year follow-up study but patients (Continued) 1604 Treatment and Follow-Up of Oral Dysplasia HEAD & NECK DOI 10.1002/hed December 2009

Table 3. Quality assessment of studies included in review (Continued). Adequacy of follow-up rate >80% Comments Blinding of outcome assessment Method of outcome assessment (cancer) Cohort characteristics Sampling method bias Assessment of exposure (dysplasia) Level of evidence Methodology and setting Study* recruited during first 3 years of study hence shorter mean follow-up tobacco habits, in excess of 50,000 villagers examined 4 Biopsy Yes Large male preponderance Medical No No Banoczy and Retrospective Csiba 29 hospital Biopsy No Yes 1 Biopsy No Sample of 6718 industrial workers in Gujarat, India Biopsy No No Excluded all mild dysplasias from follow-up Yes Sample under study was part of 50,000 patients in an oral cytology programme at university center, cancer within 12 months excluded 4 Pathology Silverman et al 30 Prospective population Mincer et al 31 Prospective hospital *Studies included in meta-analysis. MTR against study size, but there is little evidence of the asymmetry of publication bias. If the 3 outliers in the funnel plot are excluded, all of which are prospective studies, 22,30,33 the overall MTR for all studies and CI are reduced slightly (11.3%; CI: 8.4%, 15.1%). Malignant Transformation and Histologic Grade. Table 4 shows a clear difference between the transformation rate for mild to moderate dysplasia, estimated from the logistic model as 10.3%, (CI: 6.1, 16.8%), compared with severe dysplasia and CIS, and 24.1% (13.3, 39.5%; p <.008). Malignant Transformation and Treatment Modality- Patients whose lesions were not excised surgically reported considerably higher overall transformation rates when compared with patients who underwent surgical excision (14.6% vs 5.4%). After adjusting for grade in the logistic model, this was still statistically significant (p ¼.003). Time Interval to Malignant Transformation. Seven studies reported on the time interval to malignant transformation. In studies including all oral leukoplakia, this mean time interval applied to all lesions and not just lesions with dysplasia. Only 4 studies provided data specifically for dysplastic lesions (mean, 4.3 years; range, 0.5 16.0 years; data not shown). Subgroup analysis by dysplasia grade and treatment modality showed no significant differences in TMT. Relative Risk in Relation to Clinical Risk Factors. The risk factors gender, smoking status, alcohol, and site of lesions were evaluated in 4 different studies in total. From the limited data available, there appears to be a trend for malignant progression to be associated with lesions of the tongue (relative risk [RR] ¼ 1.87; CI: 1.11, 3.17), whereas continuing smoking and alcohol use after diagnosis appears to have no effect on malignant transformation (Table 5). However, the 2 studies with data on smoking are nonhomogenous (p ¼.008, Breslow-Day test). DISCUSSION Principal Findings. Oral dysplasia carries a significant rate of transformation to cancer Treatment and Follow-Up of Oral Dysplasia HEAD & NECK DOI 10.1002/hed December 2009 1605

FIGURE 2. Forest plot with calculated exact binomial confidence intervals of malignant transformation rate of oral dysplastic lesions for studies included in the meta-analysis. (12.3%). This increases considerably for highgrade dysplasia (severe dysplasia and carcinomain-situ). Furthermore, surgical excision appears to decrease the risk of transformation by more than half, but does not eliminate it. This suggests the need for continued surveillance, especially for high-grade dysplastic lesions, even after surgical excision. There was insufficient information in the studies to formally assess the effect of clinical risk factors, such as smoking and alcohol, on progression to malignancy. This systematic review demonstrated significant heterogeneity between follow-up studies. It also showed a distinct lack of randomized controlled trials examining different surgical management and follow-up protocols, especially in view of the wide variations in clinical practice that prevail in these areas. study selection, and presentation of results and discussion. 34 The possibility of publication bias remained a problem for all systematic reviews. This review was limited by the paucity of high-quality follow-up studies. The meta-analysis is therefore of the best available evidence. This may compound the methodological deficiencies of the original studies, most importantly, referral bias seen in single-center cohorts, and short followup. There are differences between the included Strengths and Limitations. This systematic review has concentrated on the long-term risk of malignant transformation and follow-up of oral dysplastic lesions. This is an area of clinical practice that showed great variability and lacks high-quality evidence. The search strategy was therefore extended to include nonrandomized studies. This systematic review complies with the MOOSE statement, which includes detailed guidelines on formulating the clinical problem, search strategy and identification of sources, FIGURE 3. Graph of the transformation rate (arcsine transformed) against study size, a form of meta-analysis funnel plot in which the study rates should lie mainly within the 95% confidence interval lines. It shows a degree of heterogeneity (they should be more clustered toward the center). The 3 outliers are Lee et al, 22 Silverman et al, 27 and Silverman et al. 30 1606 Treatment and Follow-Up of Oral Dysplasia HEAD & NECK DOI 10.1002/hed December 2009

Study* Table 4. Malignant transformation rates for all studies. Total dysplasia Mild Mod Severe CIS Malignant transform (No. of patients) Mild Mod Severe CIS MTR Hsue et al 18 166 138 15 13 NR 8 6 2 0 NR 4.8% Holmstrup et al 19 88 42 26 14 6 12 5 2 1 4 11.4% Saito et al 20 91 48 36 7 NR 7 6 1 0 NR 7.7% Cowan et al 21 158 NR 17 NR 14.5% Lee et al 22 70 61 9 NR 22 16 6 NR 31.4% Schepman et al 23 55 Not subdivided 12 Not subdivided 21.8% Lumerman et al 24 44 19 18 6 1 7 3 3 1 0 16.3% Hogewind et al 25 13 5 3 5 NR 1 0 1 0 NR 7.7% Lind 26 47 16 24 7 NR 8 1 4 3 NR 17.0 % Silverman et al 27 22 NR 8 NR 36.4% Gupta et al 28 90 NR 6 NR 6.7% Banoczy and Csiba 29 68 13 43 12 NR 9 1 3 5 NR 13.2% Silverman et al 30 35 NR 0 NR 0.0% Mincer et al 31 45 Omitted 32 13 NR 5 Omitted 2 3 NR 11.1% Abbreviations: mod, moderate; CIS, carcinoma-in-situ; MTR, malignant transformation rates; NR, not reported. studies in their design, inclusion criteria, patient population (including ethnicity), patient management, length of follow-up, and analysis of patient risk factors, all of which may have an effect on outcomes. However, combining the relatively scarce data that are available has made it possible to provide a better understanding of the overall behavior of oral dysplasia. The meta-analysis used published data and not original patient data, as many of the studies were conducted in the 1970s and 1980s. This can affect the quality of the meta-analysis. In particular, it has impeded the ability to perform subgroup analyses, especially for TMT and clinical risk factors. The former is likely to be confounded by length of follow-up and the latter by age and grade of the dysplastic lesions. It was demonstrated that there are statistically significant differences in progression rates between the various grades of oral dysplasia. However, it is widely acknowledged that histologic grading of oral dysplasia shows significant intraobserver and interobserver variability. 11 Therefore, it is impossible to be certain that the lesions included in the same grade by different studies are similar. For this reason, the subgroups mild and moderate, and severe dysplasia and CIS were almagamated. Assessment of the quality of observational studies is difficult, as there is no validated tool currently in wide use. To overcome this problem, the factors that could introduce bias into the meta-analysis were evaluated using a combination of methods. 7 10 Implications for Clinical Practice. Oral dysplasia appears to carry a significant transformation rate to oral cancer, which occurs over a period of years, even when treated by surgical excision. This would suggest that patients should be kept under surveillance after diagnosis for anything up to 20 years. It may be feasible to tailor the duration of the surveillance period, and possibly its frequency, according to several clinical Risk factor Table 5. Relative risk of malignant transformation of oral lesions analyzed by clinical risk factor. Studies reporting Risk factor present Malignant transformation Risk factor absent Malignant transformation RR (CI) Smoking (patient continues to smoke) 2 81 17 79 11 n/a Alcohol (patient continues to drink) 1 49 16 21 6 1.14 (0.52 2.51) Site (tongue vs other) 3 53 18 129 20 1.87 (1.11 3.17) Sex (male vs female) 3 78 16 83 22 0.77 (0.44 1.37) Abbreviations: RR, relative risk; CI, confidence interval; n/a, not available. Treatment and Follow-Up of Oral Dysplasia HEAD & NECK DOI 10.1002/hed December 2009 1607

factors, including grade of dysplasia, and clinical management (lesions which are not excised). However, the limited data available for this review can neither confirm nor reject the hypothesis that higher grade dysplastic lesions would transform earlier. Implications for Research. Future research is needed in 3 areas. First, research is needed in the search for better prognostic markers for progression from dysplasia to malignancy. This would replace or augment histologic grading to improve the identification of patients at risk of malignant transformation, so that they can be targeted for more aggressive treatment and closer surveillance. Second, future research is needed in the evaluation of follow-up protocols for efficacy and cost-effectiveness, including determination of surveillance duration and frequency. 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