Enucleation with or without adjuvant therapy versus marsupialization with or without secondary enucleation in the treatment of keratocystic odontogenic tumors: A systematic review and meta-analysis

Accepted Manuscript Enucleation with or without adjuvant therapy versus marsupialization with or without secondary enucleation in the treatment of keratocystic odontogenic tumors: a systematic review and meta-analysis Essam Ahmed Al-Moraissi, BDS, MSc, PhD, Assistant Professor, M. Anthony Pogrel, DDS, MD, Edward Ellis, III, DDS, MS PII:

S1010-5182(16)30072-5

DOI:

10.1016/j.jcms.2016.05.020

Reference:

YJCMS 2378

To appear in:

Journal of Cranio-Maxillo-Facial Surgery

Received Date: 29 February 2016 Revised Date:

17 April 2016

Accepted Date: 24 May 2016

Please cite this article as: Al-Moraissi EA, Pogrel MA, Ellis III E, Enucleation with or without adjuvant therapy versus marsupialization with or without secondary enucleation in the treatment of keratocystic odontogenic tumors: a systematic review and meta-analysis, Journal of Cranio-Maxillofacial Surgery (2016), doi: 10.1016/j.jcms.2016.05.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Enucleation with or without adjuvant therapy versus marsupialization with or without secondary enucleation in the treatment of keratocystic odontogenic tumors: A systematic review and meta-analysis

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Essam Ahmed Al-Moraissi, BDS, MSc, PhD1, M. Anthony Pogrel, DDS, MD2, Edward Ellis III3, DDS, MS

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1Assistant Professor, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Thamar University, Thamar, Yemen.

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2 Professor Department of Oral and Maxillofacial Surgery, University of California, San Francisco, California 3Professor and Chair, Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center, San Antonio, Texas

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Address correspondence and reprint requests to Dr Essam Ahmed Al-Moraissi

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Department of Oral and Maxillofacial Surgery, Faculty Dentistry, Thamar University, Redaa Street, Thamar, Yemen;

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e-mail:[email protected], [email protected]

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Summary The purpose of this study was to compare the recurrence rate (RR) of keratocystic

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odontogenic tumors (KOTs) in patients who underwent enucleation with or without adjuvant therapy, to patients who underwent decompression with or without residual

cystectomy. An extensive search of major databases through PubMed, EMBASE, and

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Cochrane CENTRAL was conducted to identify all relevant articles published without

date and language restrictions from inception to December 2015. Relevant articles were

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selected based on the following specific inclusion criteria. A weighted RR and odds ratio (OR) using a random with 95% confidence interval (CI) were performed. Metaregression analysis was conducted to further identify the influence of the duration of follow-up periods on the overall OR. A total of 1182 KOT patients enrolled in 14 studies were included in this analysis. There was a significant advantage for the enucleation ±

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adjuvant therapy group in preventing recurrence for patients with KOTs (OR, 0.541 mm; 95% CI, 0.302 to 0.875 mm; p = 0.001). The overall pooled weighted RR for enucleation ± adjuvant therapy and decompression ± secondary cystectomy were 18.2% and 27.1%,

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respectively. The meta-regression analysis showed that duration of follow-up time did not

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significantly influence the OR of KOT recurrence (Q = 0.506, p = 0.646). In conclusion, initial cystectomy ± adjuvant therapy were associated with fewer recurrences than decompression ± secondary cystectomy.

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INTRODUCTION

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The keratocystic odontogenic tumor (KOT), formerly known as the odontogenic keratocyst (OKC), is of odontogenic origin. Unlike odontogenic cysts, the KOT shows locally aggressive behavior, has a high recurrence rate, and has a distinct and

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characteristic histologic appearance that caused the World Health Organization (WHO) in 2005 to reclassify this lesion as a tumor instead of a cyst (Barnes et al., 2005; Kramer et

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al.,1992; Brannon, 1976).

Radiographically, displacement of impacted or erupted teeth, root resorption, root displacement, or extrusion of erupted teeth may be evident (Brannon, 1976). KOTs may occur in any part of the jaws; however, in common with ameloblastomas, calcifying

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epithelial odontogenic tumors, and myxomas, it has a predilection for the posterior body of the mandible and ascending ramus. KOTs have a peak incidence in patients between the ages of 10 and 30 years and a slight male predominance (Myoung et al., 2001;

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Maurette et al., 2006; Zhou et al., 2005). KOTs are of great interest among oral and maxillofacial surgeons because of their high recurrence rate. The current literature has

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reported a recurrence rate of 0% to 50% (Johnson et al., 2013; Johnson et al., 2012). Like other odontogenic tumors, the KOT has a tendency to expand through bony walls and to invade deeper structures (Tolstunov et al., 2008). Various treatment modalities have been used in the treatment of KOTs and can be classified as aggressive or conservative approaches. Aggressive approaches could be simple enucleation without adjuvant therapy or enucleation with adjuvant therapy, such 2

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as the application of Carnoy’s solution, cryotherapy, or peripheral ostectomy. Conservative approaches include decompression with or without subsequent residual

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cystectomy. The treatment of KOTs remains controversial, and there is no consensus as to whether an aggressive treatment is superior to conservative treatment in reducing the recurrence rate

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for treatment of patients with KOTs. Therefore, the authors of the present study tested,

through a meta-analysis, the null hypothesis that for management of patients with KOTs

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there is no difference between these treatments The specific aim of this study was to compare the recurrence rate of KOTs in patients who underwent enucleation with or without adjuvant therapies to patients who underwent decompression with or without

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residual cystectomy.

MATERIALS AND METHODS

To ensure a systematic approach and more reliable findings, this systematic review was

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conducted in accordance with the Preferred Reporting Items for Systematic reviews and

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Meta-Analyses (PRISMA) statement for reporting systematic reviews (Liberati et al., 2009).

Literature search strategy An extensive electronic search without date or language was conducted from the respective dates of inception to November 2015 using the following online databases, with specific keywords according to PICOS criteria: PubMed, Ovid MEDLINE, and

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Cochrane CENTRAL. The electronic search and the PICO strategy are shown in Table 1. The search combination of all keywords of PICOS component was (keratocystic odontogenic tumor) OR odontogenic keratocyst) OR KOT) OR okc OR kot) AND

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decompression) OR marsupialization) OR decompression followed by enucleation) OR compression followed by residual cystectomy) OR cystostomy) exteriorization) OR

fenestration) OR pouch procedure) OR Partsch operation) OR marsupialization followed

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by secondary cystectomy) AND enucleation) OR enucleation with adjuvant therapy) OR enucleation with curettage) OR enucleation plus Carnoy’s solution) OR enucleation with

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cryotherapy) OR enucleation with peripheral ostectomy) AND recurrence) AND relapse) To avoid missing any articles, the references of each selected publication that yielded from an electronic search were performed by Google Scholar and by hand.

Inclusion criteria

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Study eligibility

Inclusion criteria were adopted using the following PICOTS components. Population (P):

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adult, young and elderly patients with nonsyndromic, parakeratinized odontogenic tumors

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(virgin or recurrent) that were diagnosed and confirmed histologically. Intervention (I): Marsupialization or decompression with or without secondary cystectomy and adjunctive therapy. Comparator (C): Enucleation with or without adjunctive therapy, such as cryotherapy, peripheral ostectomy, or Carnoy’s solution. Outcome (O): Recurrence rate of KOT for the two universally accepted treatments. Time (T): Adequate follow up period (at least 1 year). Study Design (S): Prospective randomized controlled clinical trials, controlled clinical studies either prospective or retrospective, retrospective reviews, 4

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and case series comparing enucleation with or without adjuvant therapy to decompression with or without secondary cystectomy with regard to recurrence rate with an adequate

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follow-up period Exclusion criteria

The following exclusion criteria were used: animal or in vitro studies; editorial letters;

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articles in which a total number of treated KOT was less than 10; articles that did not

sufficiently specify a type of surgical method; articles that included patients with nevoid

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basal cell carcinoma syndrome (NBCCS or Gorlin-Goltz syndrome), as there can be newly developed cysts in these patients, resulting in bias when estimating recurrence rate, except for studies that specified and accounted for patients with NBCCS separately (Blanas et al., 2000;Antonoglou et al., 2014); studies that did not give an adequate

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follow-up period; and reviews articles. Data extraction process

The screening process of articles and eligibility of retrieved articles were reviewed by

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two independent reviewers. Any disagreement between the two reviewers was resolved

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by a third judge. The following data were extracted from the studies: authors, year of publication, study, male-to-female ratio, patient age (average), number of patients/lesions, location of lesion (maxilla or mandible), association with unerupted tooth, surgical treatments, follow-up period, and recurrence rate. Critical appraisal of individual studies

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Two authors (E.E and M.A) independently assessed the risk of bias for each study by using the Newcastle–Ottawa Scale (Wells et al., 2013). Disagreements were resolved by discussion or by involving the third author (E.A) to adjudicate. A study could receive a

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maximum of one star for each numbered item within the selection and outcome

categories. A maximum of two stars could be given for comparability. The greatest score that could be given to a study according to the Newcastle–Ottawa Scale was nine stars

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Summary measures and synthesis of results

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(low risk of bias). Studies scoring six stars or more were considered to be of high quality.

The recurrence rate of KOT were pooled and reported as recurrence event rate, risk ratio (RR) and odds ratio (OR) with corresponding 95% confidence intervals (95% CIs). Significant heterogeneity among the studies included for this analysis was formally

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assessed by Cochran’s χ2 test and the I2 index, where a p value <0.1 by the χ2 test and I2 value <0.25 indicate a low degree of heterogeneity; otherwise a fixed effects model with 95% confidence intervals [CI] was to be performed. In the present study, because there

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was variation of follow-up periods among the included studies, a random-effect model was used even when there was no significant heterogeneity (I2 < 50%) among the studies.

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To assess the effect of the duration of follow-up periods within the included studies, a meta-regression analysis was performed. When there were 10 included studies, an Egger funnel plot was used for analysis of the publication bias. When the p value was >0.05, there was no publication bias. The meta-analysis was conducted using a comprehensive meta-analysis software package (Biostat Inc, Englewood, NJ) (Borenstein et al., 2009).

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RESULTS Literature search

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Search outcome Figure 1 depicts the process of evaluating articles for inclusion in the review and metaanalysis. The search strategy yielded a total of 840 articles from all databases and 7

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additional articles identified thorough hand search. Of the 847 articles, 559 articles

remained after removal of duplicates. A total of 205 articles were excluded after reading

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the titles and abstracts, and the full text articles of the remaining 83 studies were reviewed independently by two authors for eligibility. At this stage of the analysis, 69 studies were excluded because of they did not meet inclusion criteria. Finally, a total of 14 studies (Maurette et al., 2006; Nakamura et al., 2002; Zhao et al., 2002;

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Chirapathomsakul et al., 2006; Driemel et al., 2007; Kolokythas et al., 2007; Madras, 2008; Boffano et al., 2010; Zecha et al., 2010; Güler et al., 2012; Selvi et al., 2012; Titinchi, 2012; Sánchez-Burgos et al., 2014; Kinard et al., 2015) met the inclusion criteria

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and were processed for critical review.

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Characteristics of included studies The details of included studies are presented in Table 2. Risk of bias within included studies No studies were given less than 6 stars. Eight studies received a total of 8 stars (Maurette et al., 2006; Nakamura et al., 2002; Zhao et al., 2002; Chirapathomsakul et al., 2006; Driemel et al., 2007; Kolokythas et al., 2007; Madras, 2008; Boffano et al., 2010; 7

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Sánchez-Burgos et al., 2014), five studies six stars (Madras, 2008; Güler et al., 2012; Selvi et al., 2012; Titinchi., 2012, Kinard et al., 2015), and one study seven stars (Zecha et al., 2010). The details of critical appraisal according to the Newcastle−Ottawa Scale

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are presented in Table 3 Results of variable outcomes

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Weighted recurrence rate

A. Enucleation with or without adjuvant therapy (Carnoy’s solutions, liquid nitrogen

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cryotherapy, and peripheral ostectomy)

A total of 843 KOT patients were enrolled in 14 studies (Maurette et al., 2006; Nakamura et al., 2002; Zhao et al., 2002; Chirapathomsakul et al., 2006; Driemel et al., 2007; Kolokythas et al., 2007; Madras, 2008; Boffano et al., 2010; Zecha et al., 2010; Güler et

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al., 2012; Selvi et al., 2012; Titinchi., 2012; Sánchez-Burgos et al., 2014; Kinard et al., 2015) that evaluated recurrence rates after treatment using enucleation alone or with Carnoy’s solutions, cryotherapy, or peripheral ostectomy. The mean follow-up period

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varied from 1 year to 25 years. There was significant heterogeneity among the studies (I2

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= 44.7%; p = 0.036). The weighted recurrence rate ranged from 14.3% to 22.2%. The overall pooled recurrence rate was 18.2% random (95% CI = 14.3%, 22.2%) (Fig. 2). B. Decompression/marsupialization with or without secondary cystectomy Fourteen studies (Maurette et al., 2006; Nakamura et al., 2002; Zhao et al., 2002; Chirapathomsakul et al., 2006; Driemel et al., 2007; Kolokythas et al., 2007; Madras, 2008; Boffano et al., 2010; Zecha et al., 2010; Güler et al., 2012; Selvi et al., 2012;

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Titinchi., 2012; Sánchez-Burgos et al., 2014; Kinard et al., 2015) with 154 KOT patients used decompression (marsupialization) either alone or followed by secondary cystectomy. There was significant heterogeneity among the studies (I2 = 27.7%; p =

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0.157). The weighted recurrence rate ranged from 18% to 38.5%. The overall pooled recurrence rate was 27.1% (random: 95% CI = 18%, 38.5%) (Fig. 3).

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Odds ratio for recurrence rate

A total of 997 KOT patients were enrolled in 15 studies (Maurette et al., 2006; Nakamura

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et al., 2002; Zhao et al., 2002; Chirapathomsakul et al., 2006; Driemel et al., 2007; Kolokythas et al., 2007; Madras,2008; Boffano et al., 2010; Zecha et al., 2010; Güler et al., 2012; Selvi et al., 2012; Titinchi., 2012; Sánchez-Burgos et al., 2014; Kinard et al., 2015) that compared enucleation ± adjuvant therapy (n = 843) to decompression ±

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secondary cystectomy (n =154). The mean follow-up period varied from 1 year to 25 years. There was a significant advantage for the enucleation ± adjuvant therapy group in recurrence prevention (OR, 0.514; 95% CI, 0.302 to 0.875; p = 0.001 [random-effects

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model]). There was no heterogeneity among studies (I2 = 0.761%; p = 0.438). The OR was 0.514, meaning that using enucleation ± adjuvant therapy in the treatment of KOTs

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decreases the incidence of recurrences by 41.4% compared with using decompression ± secondary cystectomy (Fig. 4). Linear regression of follow-up periods (mean, months) on MH odds ratio The association between duration of follow-up of included studies and recurrent KOTs (odds ratio) was investigated using a linear meta-regression. The meta-regression analysis showed that the duration of follow-up periods did not influence the recurrence rate of 9

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KOTs (Q = 0.506, p = 0.64643). The slope of the meta-regression line was a negative value, indicating that with an increase of 1 month of follow-up time, the odds ratio would decrease by 1 unit, meaning that there would be an increasing in KOT recurrence (Table

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4 and Fig. 5) Publications bias

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The funnel plot did not show any noticeable asymmetry. Accordingly, the Egger test was not significant for bias (one-tailed p = 0.34, two-tailed p = 0.68), indicating an absence of

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publication bias (Fig. 6)

DISCUSSION

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To date, there is no consensus regarding the best treatment with the lowest recurrence rate for patients with KOT. The two most universally accepted treatment options for patients with KOT are either conservative methods using marsupialization (possibly

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followed by residual cystectomy) or aggressive methods using enucleation alone (possibly followed by application or chemical cauterization, cryotherapy, or peripheral

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ostectomy).

The authors of this study hypothesized that there would be no difference between enucleation ± adjuvant therapy and decompression ± secondary cystectomy for patients with nonsyndromic KOTs. The specific aims were 1) to compare RR between two universally accepted treatments by using meta-analysis, and 2) to estimate the recurrence

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rate of KOTs after enucleation ± adjuvant therapy and decompression ± secondary cystectomy for patients with nonsyndromic KOTs.

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To the best of the authors’ knowledge, this is the first meta-analysis comparing these two treatments for the management of nonsyndromic KOTs. The predictor variable was the

treatment group, namely enucleation ± adjuvant therapy (Carnoy solution, cryotherapy,

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or peripheral ostectomy) versus decompression ± residual cystectomy.

The main finding of this study was that there was a significant advantage to the

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enucleation ± adjuvant therapy group in preventing recurrence for patients with KOTs (OR, 0.543; 95% CI, 0.364 to 0.809; p = 0.003 [random-effects model]). The OR was 0.543, meaning that using enucleation ± adjuvant therapy in the treatment of KOTs decreases the incidence of recurrences dby 35.3% compared with using decompression ±

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secondary cystectomy. This is in accorance with other literature (Maurette et al., 2008; Driemel et al., 2001; Kolokythas et al., 2007; Güler et al., 2012; Titinchi et al., 2012; Kaczmarzyk et al., 2012; Stoelinga.,2001) and in disagreement with others studies (Zhao

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et al., 2002; Madras et al., 2008; Boffano et al., 2010., Stoelinga., 2010) The overall pooled weighted recurrence rate was 17.7% for the enucleation ± adjuvant therapy groups

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and 26.5% for the decompression ± secondary cystectomy groups. This is inconsistent with previous literature (Boffano et al., 2010; Zecha., 2010; Titinchi., 2010; Wushou et al., 2014).

Part of the problem may lie in the relatively short follow-up time evident in some papers. It is well known that KOTs can recur at any time and should be followed up for at least 15−20 years. It does appear that decompression or marsupialization (there are subtle

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differences between the two34) may cause rapid resolution of the lesion, but with this treatment alone the recurrence rate is high and may approach 30% (Pogrel.,2015). Decompression plus adjuvant therapy may lower this recurrence rate, but it is believed

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that the main problem may be that as the lesion decreases in size and the cyst lining is carried forward, small remnants may be left behind, such that enucleation and further treatment of the residual cyst may not eliminate these small cell nests, which may be

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distant from the residual cyst. In contrast, enucleation of the original lesion without

decompression, with or without similar ancillary treatments, may be more effective in

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treating microextensions of the lesion that normally do not penetrate more than 1 or 2 mm. This may explain why enucleation appears to work better than decompression. There are several strengths to the present study. First, the pooling of data (meta-analysis) for included studies was thorough, using a weighted calculation of recurrence rate, that is,

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it was more accurate in representation of the incidence of an event among populations exposed to an outcome. Second, patients with NBCCS were excluded from this analysis because those patients have new lesions constantly developing, so a recurrence in a

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patient with NBCCS could be a new cyst (Johnson et al.,2013; Liberati et al.,2011).

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These factors should avoid the misleading findings and bias that have been present in some studies (Johnson.,2013; Blanas et al.,2000; Kaczmarzyk et al.,2012). How should the results of this study affect treatment of patients with KOTs? It seems appropriate that, when possible, initial enucleation with or without adjuvant therapy should be implemented. However, when doing so would jeopardize vital anatomic structures (for instance, the inferior alveolar nerve) or potentially result in fracture of the

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jaw, decompression may be a better initial option. Thus, the recurrence rate is not the

CONCLUSION

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only factor affecting the choice of treatment when confronted by a KOT.

In conclusion, initial cystectomy, with or without adjuvant therapy, is associated with the

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least chance of recurrence. A prospective, randomized, blinded, multicenter study with a long follow-up period to compare various treatments for patients with KOTs in regard to

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recurrence are strongly recommended.

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Figure 1. Study screening process Figure 2. Forest plot, enucleations ± adjuvant therapy, weighted recurrence rate.

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Figure 3. Forest plot, decompression ± residual cystectomy, weighted recurrence rate. Figure 4. Forest plot, enucleation ± adjuvant therapy versus decompression ± residual

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cystectomy, odds ratio.

Figure 5. Scatter plot of meta-regression of follow-up times (as a predictor) against the

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odds ratio (recurrence rate).

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Figure 6. Funnel plot, publications bias within included studies.

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Table 1. Search strategy for the systematic review

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Keratocystic odontogenic tumors OR kcot OR kot OR odontogenic keratocyst OR okc OR nonsyndromic keratocystics odontogenic tumuors .

Intervention

Decompression OR marsupialization OR decompression followed by enucleation OR compression followed by residual cystectomy OR cystostomy OR marsupialization followed by secondary cystectomy OR exteriorization OR fenestration OR pouch procedure OR Partsch operation

Simple enucleation OR enucleation with adjuvant therapy OR enucleation with curettage OR enucleation plus carnoy s solution OR enucleation with cryotherapy OR enucleation with peripheral ostectomy OR enucleation with liquid nitrogen cryotherapy OR enucleation with chemical cauterization Outcomes Recurrence OR relapse Study design Randomized controlled trials OR controlled clinical trials OR comparative studies OR case series Search combination Populations AND intervention AND comparator AND outcome AND study design Language No restriction Electronic data MEDLINE/PubMed and Cochrane Central Register of Controlled Trials (CENTRAL)/EMBASE base Focused question For patients with keratocystic odontogenic tumors, dose enucleation ± adjuvant therapy produce fewer recurrent KOT when compared to decompression ± residual cystectomy ?

SC

RI PT

Comparisons

AC C

EP

TE D

M AN U

MeSH, medical subject heading adjuvant.

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Table 2. Characteristics of studies included

Male/ female

Patient age (average)

No. of patients/

treatments

lesions

Mandible

NM

162 (33.13%) maxilla 327 (66.87%) mandible

173 cases (35.38%) were associated with an impacted tooth. Not recorded

Mars(5) Mars +enuc.+curettage(23) . Enuc+Cur.(15) Enuc.(163) Enuc.+CS (29) Mars.+Enuc.(11) Resection(52)

11−70 years

23

(Zhao et al., 2002)

Retrospective 1.93:1 Study

31.2 years

489 KOT in 255 patients

(Kolokythas et al., 2007)

67lesion in 51 patient

TE D

Retrospective 2:1 study

AC C

(Driemel et al., 2007)

Retrospective 0.47:1 study

30 years

EP

(Maurette et al., 2006)

M AN U

Retrospective 13:10 study

36.9 years

Retrospective 0.83:1 study

47 years

Surgical

with unerupted tooth or not

(Nakamura et al., 2002).

Retrospective 1:1.2 study

Associated

of lesion (maxilla or mandible)

ratio

(Chirapathomsakul et al., 2006)

Location

RI PT

Study design

SC

Authors

21 lesions (31.3%) Maxilla 46 lesions (68.7%) mandible

Mars (13) Enuc (30)

Case series

NM

Percentage

0 6 3 29 2 0 0

0% 26.1% 20% 17.79% 6.70% 0% 0%

1-14.6 years

1 2 1 2 0 1 7

. 16.7% 13.3% 20% 100% 0% 16% 20%

24.89 months

2

10%

0

20%

6 4 3

11,7%

6.6 years

3-29 years

Total

28 patients with 30 KOTs

12 maxilla and (16 patients, 53.3%)

86 patient with 94 KOT

18 maxilla and 76 mandible

13 of 28 patients presented impacted teeth Not record (Abstract only)

-Decom. and curettage ( 20) -Enuc.and curettage only(10)

Cystectomy (46), Mars. (6) Cystectomy and curettage (17) cystectomy and marginal ostectomy and resection (25).

Recurrence rate No. of pati ents

Enuc with CS (11) Enuc, curettage (2) Marginal resection (1) Segmental resection (6)

5,5 years

2 54-year range (18−90)

22 patients

6 maxilla and 16 mandible

Not recorded

-Resection or enuc with peripheral ostectomy (11)

Decom.with or without enuc (11)

(Madras & Lapointe 2008)

Followup period

45-year range (10−80)

21 patients (27 KOTs)

6 maxilla 21 mandible

NM

Curettage (22) Mars. (3) Resection (2)

followup of 1.5 to 9 years in group 1 and 1.5 to 3 years in group 2. 1 to7 years

0

0%

9.09% 2

6 0 0

29%, 0% 0%

ACCEPTED MANUSCRIPT 43.34-year range (7− 87)

241 patients with 261 KOTs

Zecha et al., 2010)

Retrospective 43:25 study

12−79 (39.51)

68 patients and KOCTs

(Güler et al., 2012)

Retrospective 1.4:1 study

52 years

39 patients with 43 KOTs

Retrospective 14:8 study

51 years

22

(Titinchi & Nortje 2012)

Retrospective 1:0.6 study

34.5 years

106 patients with 145 KOT 15of 106 has NBCCS

(Sánchez-Burgos et al., 2014)

Retrospective NM study

42 years

Kinard et al., 2015

Retrospective 26:19 study

43.3

55

TE D

AC C

10 maxilla (23.3%) and 33 mandible (76.7%)

5 maxilla 17 mandible

20 (46.5%) were associated with the impacted third molar NM

45 patient with 66 KOTs

Enuc + curettage (250)

36 months

11.2%

3

36%

Enuc. (58) Mars. (10)

65.1 months,

12 4

20.7% 40%

Enuc only (18)

40.45 months

No recu rren ce

0%

Enuc with CS (10) Mars. Followed by enuc. with CS (15) Enuc with curettage (20) Decom with Enuc (2)

37.8 months

Mars. (5) Enuc. (47) Enuc. +CS (8) Resection (1)

19.8 months

10(maxilla) 15 45(mandible81%)

Enuc. (42) Enuc.+CS (2) Enuc+Apicectomy (8) Mars. (3) Resection (2)

Average 5 years

53 (mandible) 13 (maxilla)

Enuc. With or without adjuvant therapy (32) Decom. With or without secondary Cystectomy (34)

30

28

Mars.(11)

36 (24.8%) 52.4% of maxilla 109 KCOT (75.2%) mandible were associated with impacted teeth,

M AN U

(Selvi et al., 2012)

70 lesions Not (26.8%), maxilla recorded and 191 KCOTs (73.2%) mandibular (ratio, 1:2.7). Maxila(16) NM Mandible (52)

RI PT

Retrospective 2:1 study

SC

(Boffano et al., 2010)

EP

*

0%

2

0% 5%

1 .3 13 0 0

50% 60% 27% 0% 0%

9 2 2 1 0

25% 100% 60& 0% 0%

10

31.13%

13

38.23%

Abbreviations: NM = not mentioned, Enuc.= enucleation, Mars = marsupialization, Decom.= decompression, KOT=keratocystics odontogenic tumor, NBCCS = nevoid basal cell carcinoma syndrome, CS = Carnoy’s solution.

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Table 3. Critical appraisal of included studies

Selections

Representati veness of exposed cohort

Ascertainm ent of exposure

Demonstration that outcome of interest was not present at start of study

(Nakamura et al., 2002). (Zhao et al., 2002) (Chirapathomsakul et al., 2006) (Maurette et al., 2006) (Driemel et al., 2007) (Kolokythas et al., 2007)

* * * * * *

* * * * * *

* * * * * *

No No No No No No

(Madras and Lapointe, 2008)

*

*

*

*

*

*

Zecha et al., 2010)

*

*

*

*

*

*

(Selvi et al., 2012)

*

*

*

(Titinchi and Nortje, 2012)

*

*

*

(Sánchez-Burgos et al., 2014) Kinard et al., 2015

* *

* *

* *

TE D

(Güler et al., 2012)

M AN U

(Boffano et al., 2010)

No

Outcomes Total no. of stars Assessm Follow-up ent of was long outcome enough for outcomes to occur#

Adequacy of follow up of cohorts

No * * * * *

* * * * * *

* * * * * *

* * * * * *

* * * * * *

8 of 8 of 8 of 8 of 8 of 8 of

*

*

*

No

No

6 of 9

SC

Consecutive or obviously representativ e series of cases

Comparability of cohorts on the basis of the design or analysis* Control for Control for NBCCS parakeratinize d entity

RI PT

Authors

9 9 9 9 9 9

No

*

*

*

*

*

8 of 9

No

*

*

*

*

No

7 of 9

No

*

*

*

No

No

6 of 9

No

*

*

*

No

No

6 of 9

No

*

*

*

No

No

6 of 9

No No

* *

* *

* *

* No

* No

8 of 9 6 of 9

A study can be awarded a maximum of one star for each numbered item within the selection and outcomes categories. A maximum of two stars can be given for comparability.

EP

# Three years of mean follow-up was chosen to be sufficient for the outcome recurrence to occur.

AC C

*Comparability was divided into follow-up of nevoid basal cell carcinoma syndrome (NBCCS) and parakeratinized entity confirmation.

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Table 4. Meta regression of the follow up periods of included studies against log odds ratio (recurrence rate)

Upper z Value limit −0.01621 −0.45873 0.66713 −0.78609

Q

df

0.21043

1

Residual

11,04962

11

Total

11,2600

12

TE D EP AC C

0.64643 0.431

p Value

0.646 0.439

M AN U

Model

p Value

RI PT

Lower limit −0.02611 −0.56062

SC

Coefficient standard errors Slope −0.00595 0.0180 Intercept −0.44675 0.56831 Tau-squared: 0.06403

0.506

RI PT

559 articles for screening after duplicate removed

M AN U

205 articles excluded after evaluation of title and abstract

EP

TE D

83 articles of full text assessed for eligibility

AC C

Eligibility Included

7 additional records identified through other source

SC

840 of records identified through electronic database

Screening

Identification

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14 articles included in qualitative and quantitative synthesis (meta-analysis)

Figure 1 : Selecting screening process

69 of records excluded due to they did not meet inclusion criteria

AC C

EP

TE D

M AN U

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RI PT

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AC C

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TE D

M AN U

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EP

TE D

M AN U

SC

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TE D

M AN U

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