Significance of Epidermal Growth Factor Receptor (EGFR) upregulation in the prediction of the malignant transformation risk in oral potentially malignant disorders: a systematic review and meta-analysis

Abstract

Objectives: The purpose of this systematic review and meta-analysis was to appraise, both quantitatively and qualitatively, the extant evidence regarding the role of EGFR upregulation in predicting malignant transformation risk associated with oral potentially malignant disorders (OPMD).

Methods: A comprehensive search was undertaken in the Web of Science, Embase, MEDLINE (via PubMed), and Scopus databases for longitudinal primary-level articles, whether prospective or retrospective in design, without restrictions on language or publication date. The QUIPS tool was employed for the purpose of assessing the potential for bias. A meta-analysis was conducted in addition to sensitivity analyses and analyses of the potential influence of small-study effects.

Results: In total, eight studies, which were treated as nine distinct units for analytical purposes, were included in the final sample, which encompassed 653 patients with OPMD with follow-up data. EGFR upregulation was found to be significantly associated with an elevated malignant transformation risk of OPMD (RR = 2.17, 95%CI = 1.73-2.73, p < 0.001). Subgroup analyses demonstrated that both EGFR protein overexpression (RR = 2.02, 95%CI = 1.55-2.63, p < 0.001) and EGFR gene amplification (RR = 2.70, 95%CI = 1.72-4.25, p < 0.001), nuclear staining (RR = 3.47, 95%CI = 1.50-8.01, p = 0.004) and the >10% cutoff point were significantly associated with transformation risk (RR = 2.27, 95%CI = 1.33-3.87, p = 0.003).

Conclusion: The present systematic review and meta-analysis demonstrates that EGFR overexpression, assessed through immunohistochemical technique, functions as a risk marker of OPMD malignant transformation risk.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024626482, identifier: CRD42024626482).

Keywords: EGFR; epidermal growth factor receptor; malignant transformation; meta-analysis; oral cancer; oral leukoplakia; oral potentially malignant disorders; systematic review.

Figure 1

Flow diagram showing the identification and selection process of relevant studies, analyzing the implications of EGFR upregulation in the prediction of the malignant transformation risk of oral potentially malignant disorders (OPMD). *eight primary-level studies systematically reviewed and meta-analyzed as nine different units of analysis.

Figure 2

Quality plot graphically representing the risk of bias (RoB) across primary-level studies using a method specifically designed for systematic reviews and meta-analyses addressing questions on prognostic factor studies (i.e., Quality in Prognosis Studies -QUIPS- tool, developed by members of the Cochrane Prognosis Methods Group). The following domains (D1–D6) were critically judged: D1, study participation; D2, study attrition; D3, prognostic factor measurement; D4, outcome measurement; D5, study confounding; and D6, statistical analysis/reporting. RoB was assessed for all domains throughout all studies and scored as potentially low (depicted as green color), moderate (yellow color), or high (red color).

Figure 3

Forest plot graphically representing the meta-analysis on the association between EGFR upregulation and malignant transformation risk in patients with OPMD. Random-effects model, DL inverse-variance weighting. Diamonds indicate the pooled RRs with their corresponding 95%CIs. EGFR, epidermal growth factor receptor; OPMD, oral potentially malignant disorders; RR, relative risk; CI, confidence intervals; DL, DerSimonian and Laird. eight primary-level studies entered into meta-analysis as nine different units of analysis, due to one study (Benchekroun et al. 2010) reported EGFR upregulation through protein overexpression and gene amplification.