Introduction
Oral lichen planus (OLP) is a common chronic inflammatory disease that usually affects the skin and mucous membranes of middle-aged women [1, 2]. Since there is a predilection for malignant transformation of OLP lesions, early diagnosis is necessary [3, 4, 5]. Angiogenesis or the formation of new blood vessels normally occurs during human evolution and reproduction; however, uncontrolled angiogenesis is a process found in a variety of pathological conditions, including cancer. Vascular endothelial growth factor (VEGF) and its receptors play a major role in angiogenesis and are often highly expressed in human cancers. Early clinical efforts to develop anti-angiogenic therapies have largely focused on inhibiting VEGF and its receptors [6]. Considering that no study has been conducted on changes in VEGF in patients with OLP and the possible malignant transformation of OLP lesions, the present meta-analysis and systematic review aims to evaluate the level of VEGF in patients with OLP.
Methods
In this systematic review and meta-analysis study, the search was conducted in online databases, including PubMed, Web of Science, and Scopus on studies published until 2021. The following search strategy was applied: (((((Oral lichen planus [Title / Abstract]) OR OLP [Title / Abstract]) OR Oral Lichenoid Lesion [Title / Abstract]))) AND (((((((Vessel endothelial growth factor [Title / Abstract]) OR VEGF [Title / Abstract]). The quality of the studies was assessed using the Newcastle-Ottawa scale [8]. The data were analyzed in the Stata v. 14 software at a 95% confidence interval (CI) using a random effect model. The standardized mean difference was used to measure the difference in the VEGF level between the two groups of OLP and controls. Heterogeneity in the results of studies was evaluated using the Chi-square test (χ2) [9]. The I2 index was used to quantify the heterogeneity [10]. Bias in the published studies was evaluated using the Begg and Egger tests [11, 12]. Sensitivity analysis was carried out to evaluate the effect of missing studies using the trim-and-fill method.
Results
A total of 6 articles were selected for the present meta-analysis [7, 14, 15, 16, 17, 18] (Table 1).


The sample size of patients with OLP, diagnosed based on clinical and histological examinations, ranged from 10 to 36. For the control group, i.e., healthy individuals without clinical presentation of OLP, the sample size ranged from 10 to 40. Among the articles, there were 2 studies conducted in Iran, and others were conducted in Egypt, China, India, and New Zealand. Two studies used the ELISA method, 3 studies used the immunohistochemistry method, and one study used the polymerase chain reaction (PCR) method to evaluate the VEGF level (Figure 1). There was no significant difference between the two groups of OLP and controls at the VEGF level (standardized mean difference=0.46, 95% CI: -2.13, -3.05) and the I2 index showed significant heterogeneity among the results of studies (I2=97.9%) (Figure 2). Based on the immunohistochemistry results, there was a significant difference in the VEGF level between the two groups (standardized mean difference=3.30, 95% CI: 6.25, -0.36), although the difference between these two groups was not statistically significant in the ELISA method (P = 0.530) (Figure 3). Discussion
The results of the reviewed studies showed that the VEGF level in patients with OLP was higher compared to the control group. In all types of OLP, an increase in VEGF was seen compared to healthy individuals. More increase occurred in patients with atrophic/erosive OLP than in patients with other forms of OLP (19,20). Since the level of VEGF in patients with OLP is higher than in healthy people, the serum factors which indicate VEGF should be considered an effective risk factor for OLP. 

Ethical Considerations
Compliance with ethical guidelines
The present study was approved by the Research Ethics Committee of Hamadan University of Medical Sciences (Ethics Code: IR.UMSHA.REC.1400.544).

Funding
This study was extracted from a research project. It was funded by the Dental Research Center of Hamadan University of Medical Sciences.

Authors' contributions
Study concept and design: Hamidreza Abdolsamadi, Mina Jazaeri; Data acquisition, analysis, or interpretation: Salman Khazaei, Laleh Shahabi; Preparing the initial draft: Laleh Shahabi, Mina Jazaeri; Critical revision of the manuscript for important intellectual content: Mina Jazaeri, Laleh Shahabi; Statistical analysis: Salman Khazzaei; Funding acquisition: Hamidreza Abdolsamadi; Supervision: Mina Jazaeri, Laleh Shahabi.

Conflicts of interest
The authors declare no conflict of interest.

Acknowledgements
The authors would like to thank the Vice-Chancellor for Research and Technology and the Dental Research Center of Hamadan University of Medical Sciences for their support.


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