Efficacy of cyclin D1 in predicting the recurrence of sporadic odontogenic keratocyst: A systematic review and meta-analysis

doi:10.21203/rs.3.rs-8470181/v1

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Systematic Review

Efficacy of cyclin D1 in predicting the recurrence of sporadic odontogenic keratocyst: A systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-8470181/v1

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Objective

The odontogenic keratocyst (OKC) is a rare and aggressive lesion with a high recurrence rate, often associated with overexpression of Cyclin D1 (CCND1). This systematic review and meta-analysis aimed to whether CCND1 can be a predictor of recurrence in OKC and to estimate the recurrence incidence rate of OKC.

Methods

The searches in PubMed, Scopus, and Web of Science databases were conducted. Eligible studies reporting recurrence rates of OKCs with sufficient follow-up data were included. The recurrence incidence rate was analyzed using a random-effect model.

Results

A total of four studies met the inclusion criteria, comprising 35 recurrence events across 113 OKCs. The pooled recurrence incidence proportion rate was 32% (0.32; CI: 0.23 to 0.40) whereas pooled recurrence incidence rate of 9% (0.09 per person-year; CI: 0.00 to 0.28). There is no clear evidence on association of CCND1 expression in predicting the recurrence.

Conclusions

We observed CCND1 expression is variably present in OKC epithelium and does not correlate with recurrence. Further, recurrence rate is very low in CCND1 positive OKCs irrespective of follow-up period. CCND1 cannot confidently predict the recurrence over the period even though CCD1 expression in noted in all OKCs.

Dentistry

Pathology

Odontogenic Keratocyst

Recurrence incidence rate

Systematic review

Meta-Analysis

GLMM

Heterogeneity Analysis

Odontogenic Keratocysts (OKCs), previously called primordial cysts, odontogenic keratocystomas, or keratocystic odontogenic tumor (KCOT), are rare, benign, and locally aggressive developmental cysts.¹ The term OKCs was finally adopted by the WHO (World Health Organization) in 2017, as it provides a better description of the condition.² They arise from the odontogenic epithelium from two primary sources: the dental lamina, its remnants, or the extension of the basal cells from the overlying oral epithelium. OKCs can be parakeratinized (having nuclei) as seen in the spontaneous, syndromic forms, or appear as orthokeratinized (lacking nuclei) odontogenic cysts. ^2–4

Sporadic OKCs are non-syndromic, isolated cysts that arise without a known genetic syndrome or family history.⁵ While many OKCs are sporadic, they can also occur as part of nevoid basal cell carcinoma syndrome (NBCCS) or Gorlin-Goltz syndrome.^3,6 The sporadic or spontaneous variant is not associated with inherited syndromes but can still harbour somatic mutations, particularly in the Sonic Hedgehog (SHH) signalling pathway.^7,8 Cyclin D1 (CCND1), found on chromosome 11q13, functions as a key positive cell cycle regulator.^9,10 Under physiological conditions, it facilitates the transition through the G1 phase, thereby promoting orderly cell cycle progression. However, dysregulated overexpression of CCND1 can result in abbreviated G1 duration, enhanced cellular proliferation, and a diminished reliance on external growth signals.^11,12 This aberrant expression pattern has been implicated in the pathogenesis of multiple benign growths and malignancies, including hepatic, pulmonary, and head and neck carcinomas.

When the SHH pathway becomes abnormally active, either because one of the regulators, the PTCH1 gene (chromosome 9p22.3 q31), is lost or the Smoothened (SMO) protein is overactive, it triggers the activation of specific proteins called GLI1 (Glioma 1) and GLI2 (Glioma 2).⁷ These GLI proteins act like switches that turn on genes that help cells grow, including CCND1.⁷ In OKCs, studies show that GLI1 directly increases the amount of CCND1, which causes cells to multiply. Available treatment options, from less invasive to more invasive, include cystostomy, marsupialization, enucleation, curettage, peripheral ostectomy, and osseous resection.^1,13 Less invasive treatment approaches are associated with lower rates of post-operative co-morbidity, but cause a higher recurrence rate of the tumor.^12–14 Multiple genetic and molecular alterations have been identified in odontogenic keratocyst. CCND1 is one of the genes to be overexpressed in OKC, however, the results of some of these studies are inconsistent, and the number of sporadic/recurrent lesions is limited.^7,15 Improving the success and clinical outcomes while reducing the chances of recurrence requires evidence-based interdisciplinary (clinical and histopathological) considerations. Therefore, this systematic review aims to present a narrative synthesis of the efficacy of CCND1 in predicting the recurrence of sporadic OKCs.

2.1. Protocol and Registration

This systematic review and meta-analysis was developed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The protocol was registered with the PROSPERO, under the registration number CRD420251014862.

2.2. Eligibility Criteria

This systematic review considered studies that examined patients diagnosed with sporadic OKCs, specifically those evaluating the expression of CCND1 using immunohistochemistry or other molecular techniques. Included studies were required to report recurrence outcomes following treatment, follow up data and to provide data that allowed for the analysis of the relationship between CCND1 expression and recurrence. Eligible designs included original research articles such as cohort studies, case-control studies, and cross-sectional studies that offered quantitative data. Studies presenting either sufficient information to construct 2 by 2 table for recurrence and CCND1 expression or Odd’s ratio for recurrence or events/ total for high and low CCND1 expression in OKCs were included.

Studies were excluded if they lacked original data such as systematic reviews, commentaries, or letters to the editor or if full-text versions were unavailable. Studies conducted in patients wherein CCND1 expression was not evaluated, as well as those failing to report recurrence outcomes or where such data could not be obtained, were also excluded. Abstract-only publications, short communications, correspondence, letter to editor and those lacking methodological robustness were not considered. No limitations were placed on language, year of publication, geographical setting, or sample size, to ensure a comprehensive and inclusive synthesis of available evidence.

2.3. Information Sources and Search Strategy

A thorough and systematic search of the literature was conducted using several major electronic databases, including PubMed (MEDLINE), Web of Science, Scopus and Cochrane. To further minimize the risk of publication bias, grey literature was actively explored. In addition, the reference lists of all included studies were carefully reviewed to identify additional relevant publications that may not have been captured through the initial database search. The search strategy was utilized a combination of MeSH and free-text keywords to encompass all relevant terminologies associated with the condition and biomarker of interest. The final search expression included terms such as “keratocyst OR parakeratinized AND odontogenic AND cyst OR kcot OR keratocystic AND odontogenic AND tumor OR odontogenic AND keratocyst OR orthokeratinized AND odontogenic AND cyst OR ooc ) AND ( cyclin AND d1 OR ccnd1).” No restrictions were applied regarding language, publication date, or article type, thereby ensuring a maximum inclusive and unbiased search.

2.4. Study Selection

All retrieved records were imported into Rayyan, a web-based platform for screening and review.¹⁶ Two reviewers independently screened titles and abstracts against the eligibility criteria. Disagreements at any stage were resolved through discussion, and if consensus could not be achieved, a third reviewer was consulted. Full-text articles were then reviewed for final inclusion. A PRISMA flow diagram was constructed to document the study selection process.

2.5. Data Extraction

Data extraction was carried out independently by two reviewers using a standardized data extraction form to ensure consistency and minimize the risk of error. For each included study, comprehensive information was recorded, encompassing the authorship, year of publication, country of origin, source of funding, and the journal in which the study appeared.

Details pertaining to the study population were documented, including the total number of participants, age distribution, gender, anatomical location of the lesion, and surgical history (if any). Methodological aspects such as the study design, techniques used to assess CCND1 expression, duration of follow-up, and statistical methods were also extracted.

The primary outcomes of interest included recurrence rates and CCND1 expression status, categorized as either positive or negative, or high versus low expression levels. In cases where relevant data were incomplete, ambiguous, or unclear, efforts were made to contact the corresponding authors for clarification to ensure data accuracy and completeness. Disagreements regarding the regarding extraction of quantitative data were resolved through discussion, and if consensus could not be achieved, a third reviewer was consulted.

2.6. Risk of Bias analysis

The ROBINS-I was used to assess the risk of bias non-randomized clinical studies. The studies were overall graded as high, Low or some concerns risk of bias.

2.7. Statistical Analysis

We planned to estimate the risk ratios (RRs) and odds ratios (ORs) for binary outcomes (yes/no) or the standardized mean difference (mean % CCND1 expression), along with 95% confidence intervals (CIs), based on data collected from studies. A comparison was conducted between the mean % expression of CCND1 in recurrence and non-recurrence cases of OKC, as well as the recurrence incidence in CCND1-positive OKCs. Given the anticipated considerable between-study heterogeneity, a random-effects inverse variance model meta-analysis was performed to pool effect sizes with 95% confidence intervals. For incidence proportion estimation, the Inverse Variance approach, Restricted Maximum-Likelihood Estimator (REML) for tau² and Hartung-Knapp (HK) adjustment method were incorporated. In the recurrence incidence proportion and recurrence incidence rate (person-year) meta-analysis, the Freeman-Tukey double arcsine transformation and logit transformation was applied, respectively. All analyses were conducted using RStudio software (RStudio 2024.12.1 + 563 "Kousa Dogwood", 2025-02-02) for macOS) with built-in meta-analysis packages. Between-study heterogeneity was assessed using Cochran’s Q test, I² statistic, and prediction intervals to evaluate variation across studies.

3.1. Characteristics of studies

A systematic search in PubMed, Scopus, and Web of Science retrieved 137 articles, of which 46 duplicates were removed. The remaining 91 articles were screened, leading to the exclusion of 70 articles based on relevance and eligibility criteria. A total of 21 full-text articles were assessed for eligibility, 17 were excluded due to incorrect study design (n = 8), different outcomes (n = 6), or incomplete data (n = 3). 4 studies met the predefined inclusion criteria and were included in review (Fig. 1). All four studies included assessed the CCND1 immunohistochemical expression and recurrence rate in sporadic OKC.^17–20 .These studies were carried out between 2015 to 2018. The included studies were conducted in Spain, Italy, Brazil, and Malaysia and involved different populations. Studies used % expression to assess the CCND1 expression in OKC. Two studies provided mean % expression of CCND1 in recurrent and non-recurrent sporadic OKC, other two did not specify the mean % expression of CCND1.

3.2. CCND1 expression in Sporadic OKC

Total 113 sporadic OKC were examined for CCND1 expression. There were 34 recurrence among these sporadic OKC. OKC commonly almost all cases of sporadic OKC were positive for CCND1, however, there was variability in expression pattern among the OKC tissue location. CCND1 expression was mostly positive in basal and parabasal cell layers in sporadic OKC. However, there is lack of data to compare the association of recurrence with CCND1 expression pattern. No study was found who correlated recurrence in OKC with high CCND1 expression with low CCND1 expression. Instead, three studies compared CCND1 expression in recurrent OKC and non-recurrent OKC. ^18,19,21 However, there was not statistical difference in CCND1 expression in OKC and non-recurrent OKC.

3.3. Meta-analysis

3.3.1. Recurrence Incidence proportion rate

Four studies provided the number of recurrence in sporadic OKC over the period of follow-up. The meta-analysis evaluated recurrence proportions across four studies, comprising 113 observations and 35 recurrence events. Individual study estimates varied, with proportions ranging from 0.23 to 0.42. The pooled recurrence incidence proportion was 0.32 (95% CI: 0.23 to 0.40) (Fig. 2). Heterogeneity was less suggesting consistency (I² = 4.8%) between the studies.

3.3.2. Recurrence Incidence Rate

The meta-analysis analyzed pooled recurrence incidence rates per person-year across four studies, identifying 35 recurrences in 113 OKCs. Studies followed OKCs patients after first treatment from 1.5 years to 9.34 Years. The recurrence rates were variable among studies, ranging from 0.04 to 0.22 per person-year, which indicates substantial differences in the likelihood of recurrence. The random-effects pooled estimate revealed an overall recurrence rate of 0.09 per person-year (95% CI: 0.002 to 0.282) (Fig. 3), emphasizing significant variability in the frequency of recurrences. The significant heterogeneity (I² = 84.4%; p = 0.0003) among the studies could be attributable to difference in study design, follow-up duration, sample sizes, and treatment.

3.4. Risk of Bias assessment

All the studies included showed a low risk of bias across the majority of the domains, indicating the strong methodology in terms of patient selection, reporting the data and the classification of the intervention. The bias in measurement of outcomes (D6) showed moderate risk across all the four included studies, this is attributed to the variations in the IHC protocol, lack of blinding, observer interpretation and outcome measurement in for the CCND1 expression. Thus, this necessitates cautious interpretation of the findings.

OKCs commonly occur in the posterior mandible, especially around the ramus and angle, and are more frequent in males, typically in the second to third decades of life.^3,22–24 They may be associated with unerupted teeth pericoronally or periapically, appear unilocular or multilocular on radiographs, and often displace adjacent teeth without root resorption. Clinically, they may cause swelling, pain, or discharge, and tend to grow anteroposteriorly.²⁵ Histologically, OKCs can present with either a parakeratinized or orthokeratinized lining, with 5–8 cell thickness, a palisaded basal layer, and no rete ridges, contributing to their high recurrence rate, especially in the parakeratinized forms.^26,27

This systematic review and meta-analysis investigated the efficacy of CCND1 in predicting the recurrence of sporadic OKC. We analyzed data from four available studies, and a meta-analysis revealed a pooled incidence of OKC recurrence to be 32% with a follow-up period ranging from 1.5 years to 9.34 Years. The findings from our review are consistent with previously documented rates in the literature, 13%-62.5%.^28,29 Our findings also align with the growing evidence suggesting that histopathological markers such as CCND1 can improve the prognostic values of sporadic OKC cases. Recent molecular insights, particularly into the SHH signalling pathway, have further illuminated the pathogenesis of OKCs, revealing the pivotal roles of PTCH1 mutations, GLI1 activation, and upregulation of CCND1, offering potential avenues for both diagnostic and therapeutic advances. ^8,30

The review also highlighted that CCND1 was positive in all recurrent OKC cases. To our knowledge, no other systematic review has examined the efficacy of CCND1 in sporadic OKC. This may be due to the paucity of original studies on the CCND1 histopathological markers. In a systematic review and meta-analysis, Kalagirou et al. reported general findings on the immunohistopathological profile of NBCCS and sporadic OKC.³¹ The recurring markers reported in the 71 reviewed original studies include CCND1, p53, Ki-67, COX-2, PTCH, and GL1. The review found markers expressed differently in the sporadic vs. the NBCCS OKC types.³¹ Interestingly, a few studies found CCND1 to be more represented in NBCCS type than the sporadic type, while other markers such as XPF, CK18, and CK18.^32–34

While an accurate diagnosis of OKC requires a mix of clinical and histopathological information, the long-term management can be more challenging.³⁵ Histological markers may provide details into the cellular behavioural pattern of an OKC but are not always foolproof. The meta-analytic results by Kalagirou et al reported that CCND1 presence in syndromic OKC has a specificity of 0.5 (95% CI 0.69–0.96) and a sensitivity of 0.87 (95% CI 0.37–0.63) with an average follow-up period of 4.1 years in the three studies used.³¹ This sheds more insight into the challenges with accurately predicting recurrence in either NBCCS or sporadic cases with CCND1, one of the most reliable markers.

Our meta-analysis further reported an overall recurrence rate of 0.09 per person-year. As management techniques improve, the potential for this incidence rate to drop increases. It is essential to reiterate the importance of adequate follow-up periods.²⁴ Patients should be informed of the need to attend these visits and that they may require additional biopsies if recurring or completely new lesions are discovered. With emerging stem cell and gene therapy research, patients may look forward to better management outcomes. Overall, our systematic review demonstrates good homogeneity within the studies and low risk of bias amongst included studies. However, a few limitations must be reported, including the paucity of studies and findings from a few centres, which may limit the generalization of findings. We call for future research to look into the efficacy of other histopathological markers in predicting the recurrence of OKCs.

The evidence concerning the relationship between CCD1 expression and recurrence prediction is inconclusive at present. CCD1 expression in the OKC epithelium exhibits variability and shows no correlation with recurrence. The recurrence rate in CCD1-positive OKCs is consistently low, regardless of the follow-up duration. Therefore, although CCD1 expression is observed in all OKCs, we cannot reliably predict recurrence over time. There is a limited number of studies and significant heterogeneity in the recurrence rates of OKCs, indicating the necessity for standardized treatment protocols and long-term monitoring strategies to reduce recurrence risks.

Acknowledgments:

Nil

Author Contributions

Conceptualization: S.P. and M.Y. Data curation: S.P., M.Y., A.C., and A.E.B. Methodology: S.P., M.Y., and A.C. Formal analysis: S.P., M.Y., and A.C. Resources: S.P., M.Y., A.E.B, and A.C. Visualization: S.P., M.Y., A.E.B, and A.C. Supervision: S.P., M.Y., and A.C. Project administration: S.P. and M.Y. Writing – original draft preparation: S.P., M.Y., A.C., and A.E.B. Writing – review and editing: M.Y., and A.C. All authors contributed to and revised the draft. All authors approved the final version of this manuscript.

Data availability statement:

The data supporting this systematic review and meta-analysis are derived from previously published studies. No new datasets were generated. All relevant data can be accessed through the original studies cited in this manuscript.

Funding statement:

Authors declared that no funding or sponsorship for manuscript

Conflict of Interest Statement:

The authors declare no conflicts of interest.

Ethics approval and Patient consent statement:

Not Applicable

Permission to reproduce material from other sources:

Not Applicable

Clinical trial registration: Not Applicable

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Tables 1 and 2 are available in the Supplementary Files section.

The authors declare no competing interests.

Table1.docx
Table 1: Characteristics of included studies in systematic review and meta-analysis of Cyclin D1 in Odontogenic keratocyst.
Table2.docx
Table 2: Number of recurrence events in total number of OKCs in each included study.

Download PDF

Version 1

posted

You are reading this latest preprint version

Efficacy of cyclin D1 in predicting the recurrence of sporadic odontogenic keratocyst: A systematic review and meta-analysis

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusions

Figures

1. Introduction

2. Methodology

2.1. Protocol and Registration

2.2. Eligibility Criteria

2.3. Information Sources and Search Strategy

2.4. Study Selection

2.5. Data Extraction

2.6. Risk of Bias analysis

2.7. Statistical Analysis

3. Results

3.1. Characteristics of studies

3.2. CCND1 expression in Sporadic OKC

3.3. Meta-analysis

3.3.1. Recurrence Incidence proportion rate

3.3.2. Recurrence Incidence Rate

3.4. Risk of Bias assessment

4. Discussion

5. Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1