RANK, RANKL, and OPG in Dentigerous Cyst, Odontogenic Keratocyst, and Ameloblastoma: A Meta-Analysis

Igor Felipe Pereira Lima Felipe Rodrigues de Matos Ítalo de Macedo Bernardino Ingrede Tatiane Serafim Santana Walbert de Andrade Vieira Cauane Blumenberg Walter Luiz Siqueira Luiz Renato Paranhos About the authors

Abstract

The aim of this study was to assess and compare RANK, RANKL, and OPG immunoexpression in dentigerous cyst, odontogenic keratocyst, and ameloblastoma. The protocol was registered in PROSPERO (CRD42018105543). Seven databases (Embase, Lilacs, LIVIVO, PubMed, Scopus, SciELO, and Web of Science) were the primary search sources and two databases (Open Grey and Open Thesis) partially captured the “grey literature”. Only cross sectional studies were included. The JBI Checklist assessed the risk of bias. A meta-analysis with random effects model estimated the values from the OPG and RANKL ratio reported by the individual studies and respective 95% confidence intervals. The heterogeneity among studies was assessed with I2 statistics. Only nine studies met the inclusion criteria and were considered in the analyses. The studies were published from 2008 to 2018. Two studies presented low risk of bias, while seven studies presented moderate risk. The meta-analysis showed the highest OPG>RANKL ratio for dentigerous cyst (ES=43.3%; 95% CI=14.3-74.8) and odontogenic keratocyst (ES=36.8%; 95% CI=18.8-56.7). In contrast, the highest OPG<RANKL ratio was found for ameloblastoma (ES=73.4%; 95% CI=55.4-88.4) and it was higher in the stromal region compared to the odontogenic epithelial region. The results may explain the aggressive potential of ameloblastoma from the higher OPG<RANKL ratio in this tumor, while it was lower for dentigerous cyst and odontogenic keratocyst.

Key Words:
odontogenic cysts; odontogenic tumors; dentigerous cyst; ameloblastoma; neoplasms

Resumo

O objetivo deste estudo foi avaliar e comparar a imunoexpressão de RANK, RANKL e OPG em cisto dentígero, ceratocisto odontogênico e ameloblastoma. O protocolo foi registrado no PROSPERO (CRD [Oculto]). Sete bancos de dados (Embase, Lilacs, LIVIVO, PubMed, Scopus, SciELO e Web of Science) foram as principais fontes de pesquisa e duas bases de dados (Open Grey e Open Thesis) capturaram parcialmente a “literatura cinza”. Apenas estudos transversais foram incluídos. A ferramenta JBI avaliou o risco de viés. Uma metanálise com modelo de efeitos aleatórios estimou os valores da razão OPG e RANKL relatados pelos estudos individuais e seus respectivos intervalos de confiança de 95%. A heterogeneidade entre os estudos foi avaliada por meio do teste I2. Apenas nove estudos preencheram os critérios de inclusão e foram considerados nas análises. Os estudos foram publicados entre 2008 e 2018. Dois estudos apresentaram baixo risco de viés, enquanto sete estudos apresentaram risco moderado. A meta-análise mostrou a maior razão OPG> RANKL para cisto dentígero (ES=43,3%; IC95%=14,3-74,8) e ceratocisto odontogênico (ES=36,8%; IC95%=18,8-56,7). Por outro lado, a maior razão OPG <RANKL foi encontrada para ameloblastoma (ES=73,4%; IC95%=55,4-88,4) e foi maior na região estromal em comparação com a região epitelial odontogênica. Os resultados podem explicar o potencial agressivo do ameloblastoma devido a uma maior proporção OPG <RANKL nesse tumor, enquanto tal proporção foi menor no cisto dentígero e no ceratocisto odontogênico.

Introduction

Odontogenic cysts and tumors constitute one of the most important lesion groups of the oral and maxillofacial complex 11 . Kouhsoltani M, Abdolhosseinzadeh M, Bahramian A, Vakili Saatloo M, Dabbaghi Tabriz F, Pourlak T. A. A Comparative Study of Macrophage Density in Odontogenic Cysts and Tumors with Diverse Clinical Behavior. J Dent 2018;19:150-154.. Odontogenic tumors are rare and manifest from various clinical features, as well as different histopathological presentations of the epithelium and odontogenic ectomesenchyme 22 . Philipsen HP, Reichart PA. Classification of odontogenic tumors. A historical review. J Oral Pathol Med 2006;35:525-529.. On the other hand, cysts originate from Malassez epithelial rests remaining from the dental blade or the reduced enamel epithelium 33 . Hume WJ, Moore JK, Main DM. Differences in in vitro growth of epithelium from inflammatory and developmental odontogenic cysts. Br J Oral Maxillofac Surg 1990;28:85-88.. One of the most significant biological events in the pathogenesis of these lesions is osteoclastic cell activation, which results in bone resorption 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253..

The balance between bone formation and resorption is required for bone homeostasis, so the tissue may fully function 55 . Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol2008;3:S131-139.,66 . Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 2008;473:139-146.. Hence, the unbalance of this system has been associated with several bone neoplasias 77 . Hofbauer LC, Neubauer A, Heufelder AE. Receptor activator of nuclear factor kappa B ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer 2001;92:460-470.. Among the regulating factors of bone resorption, the system that stands out the most is composed by the receptor activator triad of nuclear factor kappa B (RANK), nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) 88 . Yamaguchi M, Aihara N, Kojima T, Kasai K. RANKL increase in compressed periodontal ligament cells from root resorption. J Dent Res 2006;85:751-756.. The RANK works as a signaling receptor of RANKL, while the latter is expressed in the osteoblastic cells of the periodontal ligament 99 . Ogasawara T, Yoshimine Y, Kiyoshima T, Kobayashi I, Matsuo K, Akamine A, et al. In situ expression of RANKL, RANK, osteoprotegerin and cytokines in osteoclasts of rat periodontal tissue. J Periodontal Res 2004;39:42-49., binding to RANK and activating osteoclasts to promote bone resorption 1010. Stejskal D, Bartek J, Pastorková R, Ruzicka V, Oral I, Horalík D. Osteoprotegerin, RANK, RANKL. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2001;145:61-64.. On the other hand, OPG inhibits the osteoclastogenic process, blocking the RANKL and RANK binding 1111. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999;20:345-357..

A tumor may invade bone tissue and affect the balance between resorption and apposition 1212. Andrade FR, Sousa DP, Mendonça EF, Silva TA, Lara VS, Batista AC. Expression of bone resorption regulators (RANK, RANKL, and OPG) in odontogenic tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod2008;106:548-555.. Several studies 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,1212. Andrade FR, Sousa DP, Mendonça EF, Silva TA, Lara VS, Batista AC. Expression of bone resorption regulators (RANK, RANKL, and OPG) in odontogenic tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod2008;106:548-555.,1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892. have been focused on investigating the correlation of the immunologic expression of RANK, RANKL, and OPG to the development of odontogenic cysts and tumors. However, the scientific literature is still controversial regarding the expression of such proteins in the development of these lesions. Therefore, this study aimed to assess and compare, through a systematic review of the literature, the immunoexpression of RANK, RANKL, and OPG on dentigerous cyst, odontogenic keratocyst, and ameloblastoma, in order to verify whether the odontogenic keratocyst is more similar to the neoplastic or the cystic profile. The authors tested the following hypothesis: the odontogenic keratocyst will be more similar to the cystic profile.

Material and Methods

Protocol and Registration

This systematic review was performed according to the list of PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) recommendations 1515. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev2015;4:1. and the Cochrane guidelines 1616. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated in March 2011]. The Cochrane Collaboration. Available at: <Available at: http://www.handbook.cochrane.org >. Access on March 10, 2018.
http://www.handbook.cochrane.org...
. The systematic review protocol was registered in the PROSPERO database under no. CRD42018105543.

Study Design and Eligibility Criteria

This study was a systematic review that aimed to answer the following guiding question: “Is the profile of the RANKL/OPG ratio in the odontogenic keratocyst, assessed by the immunoexpression of RANK, RANKL, and OPG, more similar to the neoplastic or the cystic profile?”.

The studies included assessed the expression of the osteoclastogenic factors RANK, RANKL, and OPG in ameloblastoma, dentigerous cyst, and non-syndromic odontogenic keratocyst by immunohistochemistry, without restrictions of year, language, or publication status (In Press).

The following were excluded: 1) Studies involving inflammatory odontogenic cysts; 2) Studies not related to the topic; 3) Review studies, case reports, letters to the editor or editorials, congress abstracts, personal opinions, and books and/or book chapters; 4) Studies with high risk of bias.

Sources of Information and Search

The Embase, Latin-American and Caribbean Health Sciences Literature (LILACS), LIVIVO, PubMed (including MedLine), SciELO, Scopus, and Web of Science databases were the primary study sources. OpenThesis and OpenGrey partially captured the “grey literature”. A manual search was also performed through a systematized analysis of the references of the eligible articles. All steps aimed to minimize selection and publication biases.

The MeSH (Medical Subject Headings), DeCS (Health Sciences Descriptors), and Emtree (Embase Subject Headings) resources were used to select the search descriptors. The Boolean operators “AND” and “OR” enhanced the research strategy through several combinations (Table 1). The bibliographic research was performed in March 2019. The results obtained were exported to the EndNote Web™ software (Thomson Reuters, Toronto, Canada), in which duplicates were removed. The remaining results were exported to Microsoft Word™ 2010 (Microsoft™ Ltd, Redmond, WA, USA), in which the remaining duplicates were manually removed.

Table 1
Search strategies in the databases

Study Selection

The studies were selected in three different phases. In the first phase, as a calibration exercise, the reviewers discussed the eligibility criteria and applied them to a sample of 20% of the studies retrieved, so to determine inter-examiner agreement. After achieving a proper level of agreement (Kappa ≥ 0.81), two eligibility reviewers [IFPL and FRM] performed a methodical analysis of the titles of the studies, independently. The reviewers were not blind to the names of authors and journals. Titles not related to the topic were eliminated in this phase. In phase 2, two reviewers [IFPL and FRM] also analyzed the abstracts systematically. Studies not related to the topic, review studies, case reports, letters to the editor or editorials, congress abstracts, personal opinions, and books and/or book chapters were excluded. The studies related to the topic, but without abstracts available were fully analyzed in the third phase.

In this phase, the full texts of preliminary eligible studies were analyzed to verify whether they fulfilled the eligibility criteria. When there was no agreement in the assessment, a third reviewer [LRP] was consulted to make a final decision. The studies rejected were registered separately, explaining the reasons for exclusion.

Process of Data Collection and Extraction

After the selection, the studies were analyzed and two reviewers [IFPL and FRM] extracted their data for the following information: Identification of the study (author, year of publication, and study location); sample characteristics (number of cases); cysts and tumors assessed; ethical criteria involved; specimen fixation; diagnostic method used; immunoexpression of RANK, RANKL, and OPG; and correlation of RANKL and OPG.

To ensure the consistency among reviewers, both reviewers [IFPL and FRM] performed a calibration exercise, in which information were extracted jointly from an eligible study. The reviewers solved any disagreement through discussions, and when both reviewers disagreed, they consulted a third one [LRP] for a final decision.

Risk of Individual Bias of the Studies

The risk of bias of the studies selected was assessed by the Joanna Briggs Institute Critical Appraisal Tools for use in JBI Systematic Reviews Checklist for Analytical Cross Sectional Studies 1717. The The Joanna Briggs Institute. The Joanna Briggs Institute Critical Appraisal tools for use in JBI Systematic Reviews. Checklist for Analytical Cross Sectional Studies. Available at: Available at: https://jbi.global/sites/default/files/2019-05/JBI_Critical_Appraisal-Checklist_for_Analytical_Cross_Sectional_Studies2017_0.pdf . Latest access February 2, 2021.
https://jbi.global/sites/default/files/2...
. Two authors [IFPL and FRM] assessed each domain independently and systematically regarding their potential risk of bias, as recommended by the PRISMA-P 1515. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev2015;4:1.. The reviewers solved any disagreement through discussions, and when both reviewers disagreed, they consulted a third one [LRP] for a final decision.

The risk of bias was ranked as High when the study reached up to 49% of “yes” score, Moderate when the study reached from 50% to 69% of “yes” score, and Low when the study reached over 70% of “yes” score.

Summary Measures and Syntheses of Results

A meta-analysis using random effects estimated the pooled values calculated by the ratio between OPG and RANKL, which were reported as percentages along with the respective 95% confidence intervals and DerSimonian and Laird weights 1616. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated in March 2011]. The Cochrane Collaboration. Available at: <Available at: http://www.handbook.cochrane.org >. Access on March 10, 2018.
http://www.handbook.cochrane.org...
,1818. Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health 2014;72:39.. The random model was used to minimize the heterogeneity effect between the studies 1616. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated in March 2011]. The Cochrane Collaboration. Available at: <Available at: http://www.handbook.cochrane.org >. Access on March 10, 2018.
http://www.handbook.cochrane.org...
,1818. Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health 2014;72:39.. The variance of crude estimates was stabilized using the Freeman-Tukey double arcsine transformation 1919. Freeman MF, Tukey JW. Transformations related to the angular and square root. Ann Math Stat. 1950; 21: 607-611.. The heterogeneity among studies was assessed with I2 statistics and classified as follows: low (I2<25%), moderate (I2=50%), and high (I2>75%) 2020. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med2002;21:1539-1558.. The analyses were performed according to three different OPG and RANKL ratios (OPG>RANKL, OPG<RANKL, and OPG=RANKL), and according to two tissues (epithelium, and stroma). All estimates were assessed regarding the type of lesion. The analyses were performed with the Stata, version 15.1 (Stata Corp., College Station, USA).

Results

Study Selection

The first selection phase resulted in 245 studies distributed in nine electronic databases. After removing duplicates, 120 studies remained for the analysis of titles and abstracts. Then, after reading the titles, 15 studies continued to the analysis of abstracts. After analyzing the abstracts, only 11 studies were considered eligible for the full text reading. The references of the 11 studies were carefully assessed to check for studies retrieved through the main search strategy, but none was found. From the 11 studies included in this phase, two were removed for the following reasons: 1) use of Polymerase Chain Reaction (PCR) for the analysis; and 2) diagnostic study. Therefore, nine studies continued to the qualitative analysis of results. Figure 1 reproduces the process of search, identification, inclusion, and exclusion of articles.

Figure 1
Flowchart of the process of literature search and selection, adapted from the PRISMA statement.

Study Characteristics

Table 2 shows a summary of the main characteristics of the studies. Most part of the studies (five) 1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473. were performed in Brazil, while the other four studies were conducted in Mexico 2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531., Turkey 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253., Greece 2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551., and Malaysia 2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91.. The analysis of the nine studies resulted in a total sample of 285 specimens. From the nine studies analyzed, only three 1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237. mentioned the ethical criteria involved. As for specimen fixation, five studies 1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551. used 10% formaldehyde and four studies 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531.,2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. did not mention the means of fixation. All studies 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,212 . Philipsen HP, Reichart PA. Classification of odontogenic tumors. A historical review. J Oral Pathol Med 2006;35:525-529.,2,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551.,2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. used immunohistochemistry as the diagnostic method.

Table 2
Summary of the main characteristics of the eligible studies for qualitative analysis

Four studies 1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473. used anti-OPG (N-20; Santa Cruz Biotechnology) and anti-RANKL (N-19; Santa Cruz Biotechnology) primary polyclonal antibodies from rabbits, while two studies 2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551. used anti-OPG (H-249, scll383, Santa Cruz Biotechnology) and anti-RANKL (FL-327, sc9073, Santa Cruz Biotechnology) primary polyclonal antibodies from rabbits. One study 2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531. used anti-OPG (clone ab73400 Abcam laboratories), anti-RANK (clone 64C1385 Abcam laboratories), and anti-RANKL (clone 12A668 Abcam laboratories) antibodies. One study 2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. used primary antibodies from mice for RANK (AB13918 - Abcam Inc. Cambridge) and RANKL (AB45039 - Abcam Inc. Cambridge), and primary antibodies from rabbits for OPG (AB9986 - Abcam Inc. Cambridge). Moreover, five studies 1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. used the central lesion of giant cells as positive control. For negative control, all studies 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551.,2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. replaced the primary antibody.

Risk of Bias of Studies

Table 3 shows information regarding the risk of bias and individual quality of the studies included in this systematic review. According to the analysis of the JBI Critical Appraisal Checklist for Analytical Cross Sectional Studies 1717. The The Joanna Briggs Institute. The Joanna Briggs Institute Critical Appraisal tools for use in JBI Systematic Reviews. Checklist for Analytical Cross Sectional Studies. Available at: Available at: https://jbi.global/sites/default/files/2019-05/JBI_Critical_Appraisal-Checklist_for_Analytical_Cross_Sectional_Studies2017_0.pdf . Latest access February 2, 2021.
https://jbi.global/sites/default/files/2...
, two studies 2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551. presented low risk of bias, while seven studies 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. presented moderate risk.

Table 3
Risk of bias assessed by the JBI Critical Appraisal Checklist for Analytical Cross-Sectional Studies.

Individual Results of Studies

From the nine studies included in this systematic review, six 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531.,2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. assessed the immunoexpression of RANK and RANKL, while all studies 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551.,2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. assessed the immunoexpression of OPG. The three lesions assessed were stained for RANK in both the odontogenic epithelium and stroma. However, the immunoexpression of RANKL and OPG ranged from 0% to 100% in the odontogenic epithelium and the stroma (Table 4). The OPG>RANKL ratio ranged from 0% to 70% in the odontogenic epithelium and from 0% to 77.8% in the stroma (Fig. 2), while the OPG<RANKL ratio ranged from 0% to 50.0% in the odontogenic epithelium and from 0% to 75% in the stroma (Fig. 3). The OPG=RANKL ratio ranged from 20.0% to 60% in the odontogenic epithelium and from 0% to 90.0% in the stroma (Fig. 4).

Table 4
Immunoexpression of RANK, RANKL, and OPG

Figure 2
Forest plot showing pooled estimates for the OPG>RANKL ratio according to tissue and type of legion, considering an effect size (ES) of 95%.

Figure 3
Forest plot showing pooled estimates for the OPG<RANKL ratio according to tissue and type of legion, considering an effect size (ES) of 95%.

Figure 4
Forest plot showing pooled estimates for the OPG=RANKL ratio according to tissue and type of legion, considering an effect size (ES) of 95%.

Synthesis of Results and Meta-Analysis

Considering the OPG>RANKL ratio (Fig. 2), the highest estimate was perceived for dentigerous cyst (ES=43.3%; 95% CI=14.3-74.8) analyzed in the epithelium, although bigger, this ratio was statistically similar to that calculated for odontogenic keratocyst (ES=36.8%; 95% CI=18.8-56.7). In contrast, the highest OPG<RANKL ratio was found in ameloblastoma analyzed in the stroma tissue (ES=73.4%; 95% CI=55.4-88.4). The OPG<RANKL ratio (Fig. 3) was significantly higher for ameloblastoma in the stromal region compared to the estimate for the odontogenic epithelial region (ES=46.7%; 95% CI=28.5-65.2). Regardless of the type of lesion, the degree of heterogeneity between the studies ranged from low (I2=18.8%), when the OPG=RANKL ratio was evaluated in the epithelial region, to high moderate to high (I2=92.8%), when the same ratio was analyzed for the stromal region (Fig. 4).

Discussion

Odontogenic cysts and tumors are lesions of the oral cavity with the potential to affect the balance of the bone resorption and apposition system 1212. Andrade FR, Sousa DP, Mendonça EF, Silva TA, Lara VS, Batista AC. Expression of bone resorption regulators (RANK, RANKL, and OPG) in odontogenic tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod2008;106:548-555.. However, the scientific literature is still controversial regarding the expression of RANK, RANKL, and OPG in the development of such lesions.

The dentigerous cyst is one of the most common odontogenic cysts of the oral and maxillofacial complex. Although it is asymptomatic and rarely aggressive, in some cases it may cause significant bone expansion and teeth dislocation 2727. Ko KS, Dover DG, Jordan RC. Bilateral dentigerous cysts - report of an unusual case and review of the literature. J Can Dent Assoc 1990;65:49-51.. On the other hand, the ameloblastoma and the odontogenic keratocyst present a more invasive biological behavior with a potential destructive growth 2828. Philipsen HP, Reichart PA, Slootweg PJ. Odontogenic tumors. In: Barnes L, Eveson JW, Reichart P, Sindransky D. (eds): Pathology and genetics head and neck tumours. World Health Organization Classification of Tumours. Lyon: IARC Press 2005;283-328.. Hence, several studies 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341. have been focused on investigating the correlation of the immunologic expression of the osteoclastogenic factors RANK, RANKL, and OPG in the development of such pathologies. The present study proposed to verify whether the profile of the odontogenic keratocyst is more similar to a cystic or neoplastic lesion, which excluded inflammatory cysts from the analysis. It is worth noting that this study extracted only the results from non-syndromic odontogenic keratocysts, considering that other variables may affect the expression of RANK, RANKL, and OPG in the syndromic odontogenic keratocyst.

Immunohistochemistry is a diagnostic method that uses antibodies as specific reagents for detecting antigens in tissue and cell cut-offs, and it is often used for diagnosing neoplasias 2929. Werner B, Campos A, Nadji M, Torres LFB. Practical use of immunohistochemistry in surgical pathology. J Bras Patol Med Lab 2005; 41:353-364.. This type of technique depends on the means of specimen fixation 3030. Jaffer S, Bleiweiss IJ. Beyond hematoxylin and eosin - the role of immunohistochemistry in surgical pathology. Cancer Invest. 2004;22:445-465., for which 10% formaldehyde is mostly recommended 3131. Sampaio SAP, Rivitti EA. Histopathological examination, glossary and histopathological patterns. In: Dermatology. São Paulo: Artes Médicas 2007;123.. All the eligible studies in the present systematic review performed the immunohistochemistry technique for analyzing the expression of RANK, RANKL, and OPG, agreeing the recommendations of the scientific literature. However, only five studies 1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551. reported specimen fixation in 10% formaldehyde (Table 2).

DNA amplification reactions, as in PCR, are one of the most important molecular biology techniques today 3232. Martin J. Updating PCR. Biotechniques2019;67:3-5.. Despite this, it is a high-cost method, which involves extraction of genetic material and need experienced professionals to avoid errors inherent to the sensitivity of the technique, such as failure in amplification 3333. Assunção JGF, Correia AKA. Comparative analysis of molecular biology techniques for genotyping human papillomavirus - HPV. Revista Científica da Escola da Saúde 2014;3.. As a consequence, several laboratories find it difficult to apply it in their routine 3434. Lloveras B, Lorincz A, Ejarque M, Font R, Bosch FX, Sanjosé S. Evaluación de las técnicas de detección del VPH em los programas de cribado para cáncer de cuello uterino. Salud pública de México 2006;48:373-378.. Based on this, we only included studies that used immunohistochemistry to evaluate the immunoexpression of RANK, RANKL and OPG, because, despite being a technique with less precision than PCR, it is widely used in laboratories.

Most studies 1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551. used polyclonal antibodies to perform the immunohistochemical reaction. Polyclonal antibodies have low specificity, as they bind to different epitopes, increasing the chances of promoting a cross reaction and, consequently, generating unspecific markings 3535. Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV. Intravenous immunoglobulin for infectious diseases: back to the pre-antibiotic and passive prophylaxis era? Trends Pharmacol Science 2004;25:306-310.. The widespread use of polyclonal antibodies in studies the present systematic review may have occurred due to their low cost, when compared to monoclonal antibodies. Therefore, we believe - and strongly suggest - that monoclonal antibodies should be chosen for immunohistochemical reactions, whenever possible.

The RANK is a member of the tumor necrosis factor (TNF) receptor family 3636. Cheng X, Kinosaki M, Murali R, Greene MI. The TNF receptor superfamily: role in immune inflammation and bone formation. Immunol Res2003;27):287-294. that works as a signaling receptor of RANKL, while the latter is expressed in the osteoblastic cells of the periodontal ligament 99 . Ogasawara T, Yoshimine Y, Kiyoshima T, Kobayashi I, Matsuo K, Akamine A, et al. In situ expression of RANKL, RANK, osteoprotegerin and cytokines in osteoclasts of rat periodontal tissue. J Periodontal Res 2004;39:42-49., binding to RANK and activating osteoclasts to promote bone resorption 1010. Stejskal D, Bartek J, Pastorková R, Ruzicka V, Oral I, Horalík D. Osteoprotegerin, RANK, RANKL. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2001;145:61-64.. Thus, the RANKL, which is a protein that also belongs to the TNF family, works by regulating osteoclastic activity 3737. Kobayashi Y, Udagawa N, Takahashi N. Action of RANKL and OPG for osteoclastogenesis. Crit Rev Eukaryot Gene Expr 2009;19:61-72.. Confirming such affirmation, six studies 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531.,2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. of the present systematic review assessed the immunoexpression of RANK in dentigerous cyst, odontogenic keratocyst, and ameloblastoma, and all of them presented positive expression of RANK in both the odontogenic epithelium and stroma, reinforcing the action of this protein in the osteolytic process (Table 4).

The immunoexpression of RANKL was assessed in all the studies included in this systematic review. From the nine studies included, eight 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2323. de Moraes M, de Matos FR, de Souza LB, de Almeida Freitas R, de Lisboa Lopes Costa A. Immunoexpression of RANK, RANKL, OPG, VEGF, and vWF in radicular and dentigerous cysts. J Oral Pathol Med2013;42:468-473.,2424. Brito-Mendoza L, Bologna-Molina R, Irigoyen-Camacho ME, Martinez G, Sánchez-Romero C, Mosqueda-Taylor A. A comparison of Ki67, Syndecan-1 (CD138), and molecular RANK, RANKL, and OPG triad expression in odontogenic keratocyts, unicystic ameloblastoma, and dentigerous cysts. Dis Markers 2018; 2018: 7048531.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551. presented positive expression of RANKL in dentigerous cyst, odontogenic keratocyst, and ameloblastoma in both the odontogenic epithelium and stroma. This result corroborates the findings of the study by Qian and Zuang 3838. Qian Y, Huang HZ. The role of RANKL and MMP-9 in the bone resorption caused by ameloblastoma. J Oral Pathol Med2010;39:592-598., which assessed 24 ameloblastoma specimens and verified that RANKL was the key factor for the development of osteoclastogenesis. However, in the present systematic review, only one study 2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. did not present positive expression of RANKL for ameloblastoma, which is incompatible with the biological behavior of this pathology (Table 4). Ameloblastomas are known to be aggressive and locally invasive/destructive tumors. In some cases, bone expansion is so significant that radical resection is the only form of treatment 3838. Qian Y, Huang HZ. The role of RANKL and MMP-9 in the bone resorption caused by ameloblastoma. J Oral Pathol Med2010;39:592-598.. The referred authors of the study 2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91. suggest that the expression of RANKL may be absent because either the sample studied was a group of indolent tumors or the undergoing dynamic process was associated with bone remodeling induced by the tumor.

The OPG is a receptor of the TNF family and it is secreted by a number of cell types, including osteoblasts 3939. Pereira IA, Pereira RMR. Osteoporosis and focal bone erosions in rheumatoid arthritis: from pathogenesis to treatment. Rev Bras Reumatol. 2004;44:347-354.. This protein works by inhibiting the osteoclastogenic process, thus blocking the RANKL and RANK binding 1111. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999;20:345-357.. Hence, studies 4040. Ando K, Mori K, Rédini F, Heymann D. RANKL/RANK/OPG: key therapeutic target in bone oncology. Curr Drug Discov Technol. 2008;5:263-268.,4141. Taylan A, Birlik M, Kenar G, Toprak B, Gundogdu B, Gurler O, et al. Osteoprotegerin interacts with biomarkers and cytokines that have roles in osteoporosis, skin fibrosis, and vasculopathy in systemic sclerosis: A potential multifaceted relationship between OPG/RANKL/TRAIL and Wnt inhibitors. Mod Rheumatol 2018;25:1-6. have been developed aiming to investigate its potential as a therapeutic agent for bone diseases. All the studies included in the present systematic review assessed the immunoexpression of OPG, and immunoreactivity was not positive in only two of them 44 . Tekkesin MS, Mutlu S, Olgac V. The Role of RANK/RANKL/OPG Signalling Pathways in osteoclastogenesis in odontogenic keratocysts, radicular cysts, and ameloblastomas. Head Neck Pathol 2011;5:248-253.,2626. Siar CH, Tsujigiwa H, Ishak I, Hussin NM, Nagatsuka H, Ng KH. RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. Oral Surg Oral Med Oral Pathol Oral Radiol2015;119:83-91., whereas both verified OPG in the ameloblastoma (Table 4).

Studies 1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551. have shown that assessing the ratio of immunoexpression of RANKL and OPG is particularly important, considering it may indicate the biological activity and the osteolytic potential of the odontogenic cyst or tumor. From the nine studies included in this systematic review, five 1313. de Moraes M, de Lucena HF, de Azevedo PR, Queiroz LM, Costa Ade L. Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. Arch Oral Biol 2011;56:1256-1263.,1414. de Matos FR, de Moraes M, das Neves Silva EB, Galvão HC, de Almeida Freitas R. Immunohistochemical detection of receptor activator nuclear kb ligand and osteoprotegerin in odontogenic cysts and tumors. J Oral Maxillofac Surg2013;71:1886-1892.,2121. da Silva TA, Batista AC, Mendonça EF, Leles CR, Fukada S, Cunha FQ. Comparative expression of RANK, RANKL, and OPG in keratocystic odontogenic tumors, ameloblastomas, and dentigerous cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:333-341.,2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237.,2525. Iakovou M, Chrysomali E, Piperi E, Fanourakis G, Sklavounou A, Vlachodimitropoulos D, et al. A comparative study of bone remodeling molecules expression in different types of jaw ameloblastoma. J Oral Pathol Med2015;44:543-551. assessed such ratio. Thus, the highest OPG>RANKL ratio was found for odontogenic keratocyst and dentigerous cyst. These findings agree with the biological behavior of the odontogenic keratocyst and the dentigerous cyst, considering these are lesions with lower bone resorption ability than ameloblastoma, which is a very aggressive tumor 4242. Pozo JA, Espinoza J. Ameloblastoma uniquístico, bases del tratamiento conservador. Presentación de caso clínico y actualización bibliográfica. Revista Española de Cirugía Oral y Maxilofacial 2010;32:88-91.. It is known that RANKL binds to RANK in the surface of osteoclast precursors, recruiting and activating the tumor necrosis factor receptor-associated factor-6 (TRAF-6). Thus, the TRAF-6 stimulates the activation of the nuclear factor-kB (NF-kB) through the interaction of p62 and the atypical protein kinase C (aPKC), which triggers the transcription of osteoclastogenic genes 4343. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther 2007;9:1-7.. The NF-kB signaling is essential for osteoclastogenesis 4444. Park JH, Lee NK, Lee SY. Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells 2017;40:706-713.. Thus, the OPG inhibits the osteoclastogenic events by not allowing the binding of RANKL to RANK and preventing the entire activation cascade of NF-kB from being activated 4545. Takayanagi H. Inflammatory bone destruction and osteoimmunology. J Periodontal Res. 2005;40:287-293.. Confirming such findings, authors 1212. Andrade FR, Sousa DP, Mendonça EF, Silva TA, Lara VS, Batista AC. Expression of bone resorption regulators (RANK, RANKL, and OPG) in odontogenic tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod2008;106:548-555. verified a similar ratio with higher prevalence of OPG than RANKL in the calcifying odontogenic cyst, reinforcing the proposal of the cystic nature of the odontogenic keratocyst. Such ratio may suggest that OPG may be involved in other different biological processes of bone remodeling 2222. Nonaka CF, Cavalcante RB, Nogueira RL, de Souza LB, Pinto LP. Immunohistochemical analysis of bone resorption regulators (RANKL and OPG), angiogenic index, and myofibroblasts in syndrome and non-syndrome odontogenic keratocysts. Arch Oral Biol 2012;57:230-237..

However, the pathogenesis of the odontogenic keratocyst is still uncertain 4646. Hoyos Cadavid AM, Kaminagakura E, Rodrigues MFSD, Pinto CAL, Teshima THN, Alves FA. Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts. Clin Oral Investig 2019; 23:153-159.. The Sonic Hedgehog (Shh) activation has been indicated as one of the main mechanisms involved in the progression of this pathology 4747. Chari NS, McDonnell TJ. The sonic hedgehog signaling network in development and neoplasia. Adv Anat Pathol2007;14:344-352.. In normal cells, the Patched (PTCH) transmembrane receptor hinders Shh activation 4646. Hoyos Cadavid AM, Kaminagakura E, Rodrigues MFSD, Pinto CAL, Teshima THN, Alves FA. Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts. Clin Oral Investig 2019; 23:153-159.. However, in neoplastic cells, the Shh protein binds to the PTCH1 receptor, activating the Smoothened (Smo) transmembrane protein and inducing cell proliferation from the expression of Glioma cytoplasmic proteins (Gli-1 and Gli-2) 4848. Adolphe C, Narang M, Ellis T, Wicking C, Kaur P, Wainwright B. An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development2004;131:5009-5019.. Consequently, the NF-kB is activated, which is a signaling pathway that participates directly in the osteolytic process 4444. Park JH, Lee NK, Lee SY. Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells 2017;40:706-713.. It is known that PTCH1 works as an inhibitor of Smo in the absence of the Shh ligand. A study 4949. Ji H, Zhang X, Du Y, Liu H, Li S, Li L. Polydatin modulates inflammation by decreasing NF-kB activation and oxidative stress by increasing Gli1, Ptch1, SOD1 expression and ameliorates blood-brain barrier permeability for its neuroprotective effect in pMCAO rat brain. Brain Res Bull. 2012; 87:50-59. featuring the treatment of cerebral ischemia in rats using polydatin verified an overexpression of PTCH1 and a reduction of NF-kB, which may explain indirectly the OPG>RANKL ratio found in the odontogenic keratocyst, considering that the lower NF-kB activation implies in lower expression of RANKL and, consequently, lower osteolytic potential.

In contrast, the OPG<RANKL ratio was higher for ameloblastoma, considering the stromal region is significantly larger. The results agree with the ameloblastoma activity, considering the stromal region participates actively in the invasion and proliferation of tumor cells 5050. Fuch Fuchigami T, Koyama H, Kishida M, Nishizawa Y, Iijima M, Kibe T. Fibroblasts promote the collective invasion of ameloblastoma tumor cells in a 3D coculture model. FEBS Open Bio. 2017;7:2000-2007.. A study 5151. Kouhsoltani M, Halimi M, Jabbari G. Immunohistochemical evaluation of myofibroblast density in odontogenic cysts and tumors. J Dent Res Dent Clin Dent Prospects 2016;10:37-42. performed with the immunohistochemical marker for detecting myofibroblasts and anti-α-actin smooth muscle antibody (α-SMA) verified that from the 15 cases of solid ameloblastomas examined, only one did not express α-SMA, indicating a high myofibroblast activity in the development of ameloblastomas. Such aggressiveness from the stroma may be explained by the potential changes in the components of the mitogen-activated protein kinase (MAPK), especially in the BRAF gene, which may be activated by the fibroblast growth factor (FGF) 5252. Sweeney RT, McClary AC, Myers BR, Biscocho J, Neahring L, Kwei KA, et al. Identification of recurrent SMO and BRAF mutations in ameloblastomas. Nat Genet 2014;46:722-725.. The expression of FGF in ameloblastomas, especially FGF1, FGF2, and FGF3, are important for the positive MAPK regulation 5353. Nagi R, Sahu S, Rakesh N. Molecular and genetic aspects in the etiopathogenesis of ameloblastoma: An update. J Oral Maxillofac Pathol 2016;20:497-504.. The MAPK activation allows the phosphorylation of Raf, MEK, and ERK proteins, inducing cell proliferation 5454. Hardy KM, Yatskievych TA, Konieczka J, Bobbs AS, Antin PB. FGF signalling through RAS/MAPK and PI3K pathways regulates cell movement and gene expression in the chicken primitive streak without affecting E-cadherin expression. BMC Dev Biol2011;11:20..

Moreover, a recent study 5555. Yamada C, Aikawa T, Okuno E, Miyagawa K, Amano K, Takahata S, et al. TGF-α in jaw tumor fluids induces RANKL expression in stromal fibroblasts. Int J Oncol 2016;49:499-508. suggested that the transforming growth factor-β (TGF-β) and interleukin-1α (IL-1α) have the ability to induce the expression of RANKL in stromal fibroblasts of ameloblastomas. The positive regulation of RANKL is associated with a negative regulation of OPG, which causes the system to work in favor of osteoclastogenesis 4343. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther 2007;9:1-7.. The higher expression of RANKL allows its binding to RANK and consequently the activation of NF-kB activation, which is an essential transcription factor for the osteolytic potential of tumor lesions 4444. Park JH, Lee NK, Lee SY. Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells 2017;40:706-713.. Reinforcing these findings, authors 5656. Elias LS, Costa RF, Carvalho MA, Batista AC, Silva TA, Leles CR, et al. Markers of bone remodeling in neoplastic and bone-related lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:624-631. verified a higher immunoexpression of RANKL than OPG in osteosarcoma, which is a tumor similar to ameloblastoma regarding its aggressive and osteolytic behavior. Similarly, Sambandam et al.5757. Sambandam Y, Ethiraj P, Hathaway-Schrader JD, Novince CM, Panneerselvam E, Sundaram K, et al. Autoregulation of RANK ligand in oral squamous cell carcinoma tumor cells. J Cell Physiol2018;233:6125-6134. studied a squamous cell carcinoma sample and verified a positive regulation of RANKL, suggesting that this protein works in osteoclastic differentiation and bone destruction.

The present study is not free of limitations since immunohistochemistry is a semi-quantitative technique that, in some cases, may not be objective. Besides, there is no way to control the intensity of staining among the studies evaluated. Because of this, our systematic review did not measure the levels of staining intensity, but only the simple presence of staining. However, this study has strengths that should be considered. This is an original systematic review and meta-analysis, which used an extensive search strategy including the “grey literature”, without restrictions of language or publication status. Also, the recent classification of odontogenic cysts and tumors proposed by the WHO 5858. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. World Health Organization Classification of tumors. Pathology and Genetics of Head and Neck tumors. 4th Lyon: International Agency for Research on Cancer Press 2017; 347. establishes that the dentigerous cyst and the odontogenic keratocyst are considered odontogenic cysts, while ameloblastoma is considered a benign odontogenic tumor. Thus, this systematic review corroborates the classification proposed by the WHO. This is particularly important in clinical practice since the odontogenic keratocyst is more similar to the cystic profile, requiring greater care to perform systematic curettage technique after removal of the lesion, in order to reduce the chances of recurrence.

The results of the present systematic review suggest that the OPG<RANKL ratio was higher for ameloblastoma, which may explain its aggressive potential, and it was lower for dentigerous cyst and odontogenic keratocyst, reinforcing the WHO classification of odontogenic keratocyst as an odontogenic cyst.

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Publication Dates

  • Publication in this collection
    02 Apr 2021
  • Date of issue
    Jan-Feb 2021

History

  • Received
    30 Mar 2020
  • Accepted
    12 Aug 2020
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