Skip to main content
NCBI home page
International Dental Journal logoLink to International Dental Journal
. 2026 Jun 16;76(4):109674. doi: 10.1016/j.identj.2026.109674

Meta-Analysis and Systematic Review of Immune Checkpoint Expression in Predicting the Risk of Malignant Transformation in Oral Potentially Malignant Disorders

Yingying Cui a,#, Zihan Sima b,#, Chuanyang Ding a, Xinjia Cai a,c,⁎
PMCID: PMC13284476  PMID: 42302483

Abstract

Introduction and aims

Immune checkpoints (ICPs) play a critical role in tumour immune evasion, yet their significance in oral potentially malignant disorders (OPMDs) remains poorly defined. This study evaluates the evidence regarding ICPs in predicting malignant transformation (MT) of OPMDs and identifies research gaps.

Methods

A systematic synthesis was conducted of studies investigating ICP expression in predicting the MT risk of OPMDs. A search strategy was developed and applied across the PubMed, Scopus, and Web of Science Core Collection databases to identify articles relevant to this topic.

Results

Of the 231 publications retrieved, 5 met the inclusion criteria, encompassing a total of 613 patients, among whom 129 experienced MT, corresponding to an MT rate of 21.04%. A total of 2 ICPs were evaluated. Among these, PD-L1 was identified in several studies as having potential utility in predicting the MT risk of OPMDs. However, its clinical application requires further investigation, and clinical evidence regarding the role of other ICPs in predicting MT risk remains lacking.

Conclusion

The role of ICPs in predicting the MT risk of OPMD remains underexplored with fragmented evidence. While the PD-1/PD-L1 axis shows promise, its clinical utility remains unestablished. Prospective studies and randomized trials are further needed.

Clinical relevance

Elucidating ICP roles in OPMDs could enable precise risk stratification and immunopreventive strategies, facilitating early intervention and reducing oral cancer incidence.

Key words: Oral potentially malignant disorders, Oral leukoplakia, Immune checkpoints, PD-L1, PD-1

Introduction

Oral cancer remains a major global health challenge, with the number of cases steadily increasing to 317,500 annually.1 Despite therapeutic advances, the 5-year overall survival rate for oral squamous cell carcinoma (OSCC) remains approximately 57%.2 A key barrier to further progress in this field is the advanced stage at which most patients are diagnosed, often after tumours have already invaded surrounding tissues or metastasized, leading to a poor prognosis.3

Oral potentially malignant disorders (OPMDs) represent a group of clinically identifiable lesions that carry an increased risk of malignant transformation (MT) into oral cancer. According to the World Health Organization, OPMDs encompass conditions such as oral leukoplakia (OLK), oral submucous fibrosis (OSF), and oral lichen planus (OLP).4 Among these, oral leukoplakia is the most prevalent and extensively studied.4 However, the MT rates of OPMDs vary widely depending on lesion subtype, clinical characteristics, and population-related factors.5, 6, 7, 8, 9, 10 Current clinical management largely relies on histopathological assessment of epithelial dysplasia, yet this approach has important limitations, including interobserver variability and insufficient predictive accuracy.11, 12, 13, 14 Consequently, identifying reliable molecular or immunological biomarkers that can predict MT remains a critical unmet need in the management of OPMDs.15, 16, 17

Accumulating evidence suggests that alterations in the immune microenvironment play a crucial role in the progression of premalignant lesions toward invasive cancer.18 In particular, immune checkpoint (ICP) molecules, which are key regulators of immune activation and tolerance, have emerged as important mediators of tumour immune evasion.19 Molecules such as programmed cell death protein-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and other inhibitory receptors are increasingly recognized for their roles in suppressing antitumor immune responses and facilitating tumour progression.19 While immune checkpoint inhibitors (ICIs) are effecting a paradigm shift in the treatment landscape of several malignancies, including head and neck cancers,20, 21, 22 the role of ICP expression during the early stages of oral carcinogenesis remains incompletely understood.

Recent studies have reported aberrant expression of ICP in OPMDs and have suggested potential associations with epithelial dysplasia severity, immune microenvironment remodelling, and MT risk.23, 24, 25 However, the available evidence is fragmented, and the reported findings are often inconsistent due to differences in study design, sample size, biomarkers assessed, and detection methods. To date, no comprehensive synthesis of the existing literature has systematically evaluated the relationship between ICP expression and the risk of oral cancer in patients with OPMDs.

Therefore, a systematic evaluation of current evidence is needed to clarify the potential predictive and biological significance of ICP in OPMDs. In this context, the present meta-analysis aims to summarize and critically assess the available studies investigating ICP expression in OPMDs and its association with the risk of oral cancer development. By integrating current evidence, this review seeks to provide insights into the immunological mechanisms underlying MT and to explore the potential of ICP as biomarkers for risk stratification and early intervention in patients with OPMDs.

Materials and methods

The protocol and registration

This systematic review was conducted in accordance with the guidelines outlined in the PRISMA checklist 26 and has been registered with the identifier CRD420261341263.

Eligibility criteria

To formulate the core research questions and establish the inclusion criteria for this systematic review, we adopted the PECOS (participants, exposure, comparison, outcomes, and studies) framework, following methodologies established in the previous study.15,27,28 The specific criteria were defined as follows, participants: patients diagnosed with OPMDs based on clinical and histopathological evaluation; exposure: assessment of any altered ICP molecules in human OPMD specimens; comparison: reported expression levels of the ICP; outcomes: association with MT of OPMDs; studies: randomized clinical trials, prospective or retrospective cohort studies, case–control studies, and cross-sectional studies. No restrictions were imposed regarding sex, age group, or geographic origin. Studies were excluded based on the following criteria: (1) review articles, systematic reviews, meta-analyses, case reports, conference abstracts, book chapters, opinions, and letters to the editor; (2) studies involving in vitro experiments or animal models; (3) investigations focusing on anatomical sites other than the oral cavity without separately reporting oral data; and (4) studies lacking information on MT.

Search strategy and data extraction

A comprehensive literature search was performed using the following electronic databases: PubMed, Scopus, and Web of Science Core Collection. The search strategy was developed based on Medical Subject Headings (MeSH) terms and informed by previous systematic review experience, with the detailed strategy provided in Table S1. The search was conducted from the inception of each database until March 13, 2026, when the final search was executed. Additionally, we manually screened the reference lists of included studies to identify potentially relevant articles published during this period. Reference management and duplicate removal were performed using reference management software. Two authors (Y.C. and Z.S.) independently screened the titles and abstracts of all retrieved articles during the initial phase, followed by a full-text review of potentially eligible studies. Any discrepancies between the two reviewers were resolved through consultation with a third author (X.C.). Data extracted from each eligible study were compiled into a standardized data extraction form. The dataset encompassed various variables, including study source, author names, publication year, country, types of OPMDs, specific ICP molecules investigated, detection and quantification methods, and prognostic value, particularly the association with MT as reported through univariate or multivariate analyses (Table S2).

Risk of bias assessment

To evaluate the risk of bias (RoB) in individual studies, we employed the Quality in Prognosis Studies (QUIPS) tool.29 This assessment considered the following key domains: study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, and statistical analysis and reporting. Two independent reviewers (Y.C. and C.D.) performed the RoB assessment, with any disagreements resolved through discussion and, if necessary, adjudication by a third reviewer (X.C.).

Data synthesis and statistical analysis

A qualitative synthesis was conducted to summarize the findings, focusing on ICP expression, oral cancer-free survival metrics, and hazard ratios (HRs). Where sufficient homogeneity existed among studies reporting on comparable ICP-related variables, a quantitative meta-analysis was planned to pool the effect estimates.

Results

Study selection and general characteristics

A total of 231 publications were initially identified through the literature search. Following the screening of titles and abstracts, 221 publications were excluded for duplicating documents and failing to meet the inclusion criteria. After a full-text review, an additional 5 studies were excluded, ultimately resulting in the inclusion of 5 studies in this systematic review (Table S2). The detailed literature selection process is presented in the Figure. The included studies comprised 1 prospective cohort study 30 and 4 retrospective cohort studies.31, 32, 33, 34 Collectively, these studies enrolled 613 patients diagnosed with OPMDs. During the follow-up period, MT occurred in 129 patients (MT rate of 21.04%). The geographical distribution of the included studies spanned multiple regions: Asia (Japan, n = 2; China, n = 1), North America (United States, n = 1), and Europe (Germany, n = 1). Due to the heterogeneity in reporting across studies and missing data, it was not feasible to aggregate pooled information on sex, age, tobacco and alcohol consumption, lesion sites, or epithelial dysplasia grading.

Fig.

Fig dummy alt text dummy alt text

Open in a new tab

PRISMA flowchart.

Immune checkpoints expression and risk of malignant transformation

This systematic review evaluated the expression of 2 ICP molecules: programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1). The included studies were required to have assessed the prognostic value of these molecules using at least one of the following methods: Kaplan–Meier curve analysis or Cox regression analysis. Among the 5 included studies, only 2 performed multivariable analyses (Table S2). Three studies demonstrated that positive or high expression of the PD-L1 protein, whether in the epithelium or the subepithelial layer, was associated with MT in OPMD.30,32,34 One study reported a significant association between high PD-1 protein expression and MT, without specifying the localization of the expression.31 In contrast, 1 study found no correlation between MT and PD-L1 mRNA, PD-L1 protein, or PD-1 protein expression in OPMD, irrespective of whether the expression was assessed in the epithelium or the subepithelial layer.33

Detection of immune checkpoints expression

According to the included studies, 4 articles performed immunohistochemical staining to assess PD-L1 protein expression, 1 study conducted immunofluorescence assays for PD-L1, and 1 study analysed PD-L1 mRNA expression in formalin-fixed paraffin-embedded (FFPE) tissue sections using a commercially available extraction kit. For PD-1, two studies employed immunohistochemistry to evaluate its protein expression. Detailed information regarding the specific PD-L1 and PD-1 antibodies used, as well as the corresponding quantification methods for each study, is provided in (Table S2).

Risk of bias within individual studies

The QUIPS tool was utilized to assess the potential RoB within individual studies (Table S3). Overall, the most frequent assessment across all domains was low RoB (50%). Specifically, all studies were uniformly rated as having a low RoB in the domains of 'study attrition' and 'prognostic factor measurement'. The majority of studies were judged to have a moderate RoB in the domains of 'study participation' (80%) and 'outcome measurement' (100%). Conversely, higher proportions of studies were classified as having a high RoB in the domains of 'study confounding' (60%) and 'statistical analysis and reporting' (40%). These biases primarily stemmed from methodological shortcomings, including: a lack of sample size or power calculations, ambiguous types of OPMD under investigation, unreported or unclear follow-up durations, insufficiently defined clinical and histopathological criteria for confirming MT, and the absence of multivariable Cox regression analyses that adequately accounted for potential confounders or covariates.

Risk of bias across studies

Substantial heterogeneity was observed among the included studies. This heterogeneity originated from several factors, most notably the lack of standardized methods for detecting and quantifying ICP expression, as well as the use of inconsistent evaluation metrics. Discrepancies were also noted in the protocols for follow-up assessments and the reporting methodologies across studies. Regarding outcomes, HRs derived from Cox regression analyses, and particularly from multivariable analyses, were infrequently reported and exhibited a lack of consistency. Furthermore, the study populations were predominantly based on convenience sampling, introducing considerable heterogeneity and limiting the generalizability of the findings. The specific types of OPMD included also varied across the studies. In view of the substantial methodological and clinical heterogeneity identified, a pooled analysis from the included studies was deemed inappropriate and was therefore not conducted.15,35

Discussion

The present study provides a systematic review of the current landscape regarding the role of ICPs, particularly PD-1 and PD-L1, in the MT of OPMDs. While the prognostic and predictive value of these ICP molecules has been extensively investigated in head and neck cancer, their significance in the premalignant stage remains inadequately defined. Our findings reveal a complex and, at times, contradictory body of evidence, underscoring both the promise and the limitations of current research in this area.

MT represents the most serious adverse prognostic outcome of OPMD, and consequently, the identification of biomarkers for this process has attracted considerable research interest. Several meta-analyses have been conducted to evaluate the clinical value of prognostic markers in OPMD; however, most have focused on markers of cell proliferation (eg, p53), cell adhesion and junction (eg, podoplanin), and genomic instability (eg, copy number alterations).15, 16, 17,36, 37, 38, 39 Although the clinical relevance of immune checkpoint proteins (ICPs) as prognostic markers has been analysed in oral cancer,40 there remains a lack of evidence-based data regarding their role in predicting the risk of MT in OPMD. One of the key observations is the inconsistency surrounding PD-L1 as a predictive biomarker for the MT risk of OPMD. Although several studies have reported a positive correlation between PD-L1 expression and increased MT potential,30,32,34 1 study yielded negative results.33 Such discrepancies may be attributed to several factors, including differences in study design, sample size, antibody clones used for immunohistochemistry, scoring systems, and heterogeneity in the histopathological classification of OPMD subtypes. These variations highlight the pressing need for standardized methodologies and multicentre validation cohorts to establish the true predictive value of PD-L1.

From a clinical perspective, PD-L1 expression holds considerable promise as a biomarker to improve risk stratification in OPMD and contributes to real-world clinical decision-making. If validated in larger, well-standardized cohorts, PD-L1 could serve as an adjunctive indicator for identifying high-risk lesions that may not be fully captured by conventional dysplasia grading alone.12 In this context, patients with elevated PD-L1 expression might benefit from more intensive surveillance, including shorter follow-up intervals, more frequent clinical examinations, and earlier re-biopsy when subtle changes are observed. Conversely, lesions with low PD-L1 expression could be managed with less frequent monitoring, thereby optimizing resource allocation in routine dental practice. However, there is a lack of prospective studies with rigorous follow-up protocols. While the PD-1/PD-L1 axis is promising, the current lack of extensive data necessitates caution in drawing definitive clinical conclusions.

Due to the total absence of data, the roles of other immune checkpoints such as CTLA-4, LAG-3, and TIM-3 in MT of OPMD remain unexplored. Our analysis identified no studies meeting inclusion criteria that systematically evaluated these markers in the context of OPMD progression. This stands in stark contrast to the well-documented involvement of these molecules in the tumour immune microenvironment of OSCC.40,41 The absence of such investigations represents a significant research gap, particularly given the emerging interest in combination immunotherapies targeting multiple checkpoints. It is plausible that certain ICPs may play distinct roles during the early stages of carcinogenesis, potentially serving as earlier indicators of immune evasion analogous to PD-1/PD-L1. Further studies should therefore broaden their scope to include a panel of ICPs, employing multiplex immunohistochemistry or single-cell technologies to dissect the spatial and temporal dynamics of immune cell infiltration and checkpoint expression across the spectrum of OPMD progression.

The differential expression patterns of ICPs across OPMD subtypes, such as OLK, OSF, and OLP, also warrant careful consideration. In OLK, a relatively consistent pattern has emerged, with PD-L1 expression showing a negative correlation with CD8+ T cells and a positive correlation with CD163+ macrophages, suggesting a shift toward an immunosuppressive microenvironment as dysplasia advances.42 Moreover, the observed progressive increase in PD-1 and PD-L1 expression from normal mucosa through OLK to OSCC, coupled with their correlation with the severity of epithelial dysplasia, supports a model in which ICP upregulation parallels histopathological deterioration.23 This is further corroborated by in vivo evidence demonstrating that PD-1 blockade can activate CD8+ T cells and attenuate epithelial dysplasia, providing a mechanistic rationale for early immunotherapeutic intervention.23 However, it is important to note that these findings are derived primarily from preclinical models and small-scale clinical studies; the translational potential of such interventions awaits confirmation in randomized controlled trials.

In contrast, the roles of ICPs in OLP and OSF remain poorly characterized.43,44 Unlike OLK, which is widely recognized as a classical precancerous lesion, OLP has more ambiguous MT potential, with distinct etiopathogenesis and immune profiles. OLP is characterized by a predominantly T-cell-mediated inflammatory infiltrate, whereas OSF involves chronic inflammation driven by areca nut exposure, often accompanied by fibrosis and variable degrees of epithelial dysplasia. Whether ICPs contribute to or predict MT in these entities remains unclear. The scarcity of dedicated studies focusing on OLP and OSF may reflect the historical emphasis on OLK as a model for oral carcinogenesis, yet given the rising global prevalence of OSF in regions with areca nut consumption,45 further investigations should prioritize these understudied OPMD subtypes, employing longitudinal cohort designs to elucidate whether specific ICP signatures confer increased MT risk or serve as therapeutic targets.

Genomic aberrations, particularly copy number alterations, have emerged as another layer of complexity in understanding ICP biology in OPMD progression. The association between 9p arm deletion, PD-L1-JAK2 codeletion, and resistance to PD-1 inhibitors, as reported by William et al,46 introduces a compelling genetic dimension to the field. These findings are consistent with observations from clinical trials linking 9p copy number loss to poor response to anti-PD-1 therapy.47 Notably, prior studies have implicated copy number alterations in both the malignant transformation of OLK and the severity of epithelial dysplasia, with artificial intelligence-based approaches further corroborating these associations.14,48, 49, 50, 51 The convergence of genomic and immunological evidence suggests that chromosomal instability may shape the immune landscape from the earliest stages of carcinogenesis. Elucidating the causal relationships between specific genomic variants, ICP expression, and response to ICIs will be essential for developing predictive biomarkers and guiding patient selection for immunopreventive strategies.

Therapeutic applications of ICIs in OPMDs represent an emerging but rapidly evolving area. The pioneering study by Hanna et al, which evaluated nivolumab in patients with high-risk proliferative verrucous leukoplakia, demonstrated that PD-1 inhibition can achieve clinical and pathological improvement in a subset of patients, with a 2-year cancer-free survival rate of 73%.47 Despite these encouraging results, the lack of a randomized control group precludes definitive conclusions regarding efficacy. Furthermore, the absence of correlation between PD-L1 combined positive score and treatment response underscores the limitations of current biomarker strategies and highlights the need for more refined predictive indicators. Ongoing investigations, such as that by Gurizzan et al exploring avelumab, a PD-L1-blocking monoclonal antibody, may contribute valuable insights into the therapeutic potential of ICP blockade in OPMDs.52 However, several questions remain unanswered, including optimal patient selection criteria, treatment duration, long-term safety profiles, and the potential need for combination strategies targeting multiple ICPs or incorporating conventional chemopreventive agents.

Several limitations of this study should be acknowledged. First, only English-language publications were included, and studies published in other languages were not considered. Second, considerable heterogeneity and limited subgroup data were observed among the 5 included studies, precluding a pooled or subgroup analysis. Moreover, two of the included studies originated from the same research group, raising the possibility of overlapping data. Additionally, most of the included studies were limited to univariate analyses, which may diminish the generalizability of the findings. Notwithstanding these limitations, the role of ICPs in the MT of OPMDs warrants further investigation.

Collectively, the evidence reviewed here paints a picture of a field at an early stage of maturation. Despite accumulating data supporting the involvement of ICPs in OPMD biology, substantial gaps persist. The predictive value of PD-L1 remains contested, the roles of other ICPs are largely unexplored, and the heterogeneity across OPMD subtypes has been inadequately addressed. Moreover, the scarcity of prospective, well-controlled studies with robust follow-up limits the generalizability and clinical applicability of existing findings. To advance the field, further research should prioritize the following directions. Given the considerable heterogeneity in PD-L1 scoring systems, adopting a standardized IHC protocol would enhance cross-study comparability and consolidate the evidence for PD-L1 as a biomarker of MT in OPMD. Second, implementation of large-scale, prospective cohort studies with long-term follow-up to delineate the natural history of ICP expression and its association with MT. Moreover, integration of multi-omics approaches, including genomics, transcriptomics, and spatial proteomics, to unravel the complex interplay between genetic alterations and immune microenvironment dynamics. Furthermore, rigorous evaluation of ICIs-based interventions in randomized controlled trials to establish efficacy, safety, and predictive biomarkers for patient stratification.

Conclusions

In summary, the role of ICPs in predicting the MT of OPMDs remains an underexplored frontier. While several evidence points to the potential of PD-L1 axis as a biomarker, significant uncertainties persist. Addressing these gaps will require concerted efforts to overcome methodological heterogeneity, expand investigations to understudied OPMD subtypes and alternative ICPs, and generate high-level evidence through prospective, controlled studies. Only through such comprehensive approaches can the field move closer to translating ICP biology into clinical strategies that reduce the burden of oral cancer through early detection and intervention.

Author contributions

Y.C. & Z.S. contributed to data curation, formal analysis, investigation, methodology, resources, software, validation, visualization, writing – original draft. C.D. contributed to formal analysis, investigation, methodology, resources, software, validation, visualization, writing – review & editing. X.C. contributed to conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, supervision, validation, writing – original draft, & writing – review & editing.

Funding

This work was supported by Beijing Science & Technology Development of Traditional Chinese Medicine BJZYQN-2025-11, China Postdoctoral Science Foundation 2025M781685 and GZB20240038, China Oral Health Foundation COHF-KQZS2026023, Talent development plan for the future in Medical-Engineering Integration by BRA-CDCHE and ZTA MBRC0012025013, State Key Laboratory of Innovative Immunotherapy.

Conflict of interest

None disclosed.

Footnotes

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.identj.2026.109674.

Appendix. Supplementary materials

mmc1.docx (24.5KB, docx)

REFERENCES

  • 1.Rumgay H., Colombet M., Ramos da Cunha A., et al. Global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2022. CA Cancer J Clin. Jan-2026;76(1) doi: 10.3322/caac.70048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Cai X., Zhang J., Jing F., Zhou X., Zhang H., Li T. Clinical and prognostic features of multiple primary cancers with oral squamous cell carcinoma. Arch Oral Biol. 2023;149 doi: 10.1016/j.archoralbio.2023.105661. [DOI] [PubMed] [Google Scholar]
  • 3.Cai X., Huang J. Distant metastases in newly diagnosed tongue squamous cell carcinoma. Oral Dis. 2019;25(7):1822–1828. doi: 10.1111/odi.13147. [DOI] [PubMed] [Google Scholar]
  • 4.Warnakulasuriya S., Kujan O., Aguirre-Urizar J.M., et al. Oral potentially malignant disorders: a consensus report from an international seminar on nomenclature and classification, convened by the WHO collaborating centre for oral cancer. Oral Dis. 2021;27(8):1862–1880. doi: 10.1111/odi.13704. [DOI] [PubMed] [Google Scholar]
  • 5.Meci A., Goyal N., Goldenberg D. Malignant transformation rate of oral premalignant disorders: a large database analysis. Laryngoscope. 2025;135(10):3654–3659. doi: 10.1002/lary.32236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Lorezo-Pouso A.I., Lafuente-Ibanez de Mendoza I., Perez-Sayans M., et al. Critical update, systematic review, and meta-analysis of oral erythroplakia as an oral potentially malignant disorder. J Oral Pathol Med. 2022 doi: 10.1111/jop.13304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Gilvetti C., Soneji C., Bisase B., Barrett A.W. Recurrence and malignant transformation rates of high grade oral epithelial dysplasia over a 10 year follow up period and the influence of surgical intervention, size of excision biopsy and marginal clearance in a UK regional maxillofacial surgery unit. Oral Oncol. 2021;121 doi: 10.1016/j.oraloncology.2021.105462. [DOI] [PubMed] [Google Scholar]
  • 8.Cai X., Zhang J., Han Y., Tang Q., Zhang H., Li T. Development and validation of a nomogram prediction model for malignant transformation of oral potentially malignant disorders. Oral Oncol. 2021;123 doi: 10.1016/j.oraloncology.2021.105619. [DOI] [PubMed] [Google Scholar]
  • 9.Iocca O., Sollecito T.P., Alawi F., et al. Potentially malignant disorders of the oral cavity and oral dysplasia: a systematic review and meta-analysis of malignant transformation rate by subtype. Head Neck. 2020;42(3):539–555. doi: 10.1002/hed.26006. [DOI] [PubMed] [Google Scholar]
  • 10.Ding C., Cui Y., Li T., Cai X. Scientific mapping and knowledge evolution of global areca research. Int dent j. 2026;76(1) doi: 10.1016/j.identj.2025.109342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Sperandio M., Warnakulasuriya S., Soares A.B., et al. Oral epithelial dysplasia grading: comparing the binary system to the traditional 3-tier system, an actuarial study with malignant transformation as outcome. J Oral Pathol Med. 2022 doi: 10.1111/jop.13365. [DOI] [PubMed] [Google Scholar]
  • 12.Odell E., Kujan O., Warnakulasuriya S., Sloan P. Oral epithelial dysplasia: Recognition, grading and clinical significance. Oral Dis. 2021;27(8):1947–1976. doi: 10.1111/odi.13993. [DOI] [PubMed] [Google Scholar]
  • 13.Tilakaratne W.M., Jayasooriya P.R., Jayasuriya N.S., De Silva R.K. Oral epithelial dysplasia: causes, quantification, prognosis, and management challenges. Periodontol 2000. 2019;80(1):126–147. doi: 10.1111/prd.12259. [DOI] [PubMed] [Google Scholar]
  • 14.Cai X., Zhang J., Zhang H., et al. Architectural and cytological features of epithelial dysplasia associated with transformation risk. Oral Dis. 2024;30(5):3028–3038. doi: 10.1111/odi.14809. [DOI] [PubMed] [Google Scholar]
  • 15.Monteiro L., Rocha E., Ferreira S., Salazar F., Pacheco J.J., Warnakulasuriya S. Tissue biomarkers for predicting the risk of oral cancer in patients diagnosed with oral leukoplakia: a systematic review of the past 4 years. J Oral Pathol Med. 2025;54(5):283–289. doi: 10.1111/jop.13632. [DOI] [PubMed] [Google Scholar]
  • 16.Monteiro L., Mello F.W., Warnakulasuriya S. Tissue biomarkers for predicting the risk of oral cancer in patients diagnosed with oral leukoplakia: a systematic review. Oral Dis. 2021;27(8):1977–1992. doi: 10.1111/odi.13747. [DOI] [PubMed] [Google Scholar]
  • 17.Celentano A., Glurich I., Borgnakke W.S., Farah C.S. World Workshop on Oral Medicine VII: Prognostic biomarkers in oral leukoplakia and proliferative verrucous leukoplakia-A systematic review of retrospective studies. Oral Dis. 2021;27(4):848–880. doi: 10.1111/odi.13363. [DOI] [PubMed] [Google Scholar]
  • 18.Hanahan D. Hallmarks of cancer-Then and now, and beyond. Cell. 2026 doi: 10.1016/j.cell.2025.12.049. [DOI] [PubMed] [Google Scholar]
  • 19.Kroemer G., Chan T.A., Eggermont A.M.M., Galluzzi L. Immunosurveillance in clinical cancer management. CA Cancer J Clin. 2023 doi: 10.3322/caac.21818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Saba N.F., Wong S.J., Nasti T., et al. Intensity-modulated reirradiation therapy with nivolumab in recurrent or second primary head and neck squamous cell carcinoma: a nonrandomized controlled trial. JAMA Oncol. 2024 doi: 10.1001/jamaoncol.2024.1143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Machiels J.P., Tao Y., Licitra L., et al. Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2024;25(5):572–587. doi: 10.1016/s1470-2045(24)00100-1. [DOI] [PubMed] [Google Scholar]
  • 22.Zhang W., Gan M., He Y., Ma W., Liu S., Liu D. Nanoplatform-enhanced photodynamic therapy in head and neck squamous cell carcinoma: advances and future directions. Int Dent J. 2026;76(1) doi: 10.1016/j.identj.2025.109348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Dong Y., Wang Z., Mao F., et al. PD-1 blockade prevents the progression of oral carcinogenesis. Carcinogenesis. 2021;42(6):891–902. doi: 10.1093/carcin/bgab035. [DOI] [PubMed] [Google Scholar]
  • 24.Kujan O., Agag M., Smaga M., et al. PD-1/PD-L1, Treg-related proteins, and tumour-infiltrating lymphocytes are associated with the development of oral squamous cell carcinoma. Pathology. 2022;54(4):409–416. doi: 10.1016/j.pathol.2021.09.013. [DOI] [PubMed] [Google Scholar]
  • 25.Cai X., Li L., Yu F., et al. Development of a pathomics-based model for the prediction of malignant transformation in oral leukoplakia. Lab Invest. 2023;103(8) doi: 10.1016/j.labinv.2023.100173. [DOI] [PubMed] [Google Scholar]
  • 26.Shamseer L., Moher D., Clarke M., et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350 doi: 10.1136/bmj.g7647. [DOI] [PubMed] [Google Scholar]
  • 27.Wahyudi R., Aguilar P., Changsiripun C., et al. Inflammatory biomarkers in irreversible pulpitis and pulp necrosis: a systematic review and meta-analysis. Int Dent J. 2026;76(2) doi: 10.1016/j.identj.2026.109453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Taha J., Veettil S.K., Panda S., Gopinath D. Human papillomavirus infection as a risk factor for oral leukoplakia: a systematic review and meta-analysis. Int Dent J. 2025;75(6) doi: 10.1016/j.identj.2025.103944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Hayden J.A., van der Windt D.A., Cartwright J.L., Côté P., Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med. 2013;158(4):280–286. doi: 10.7326/0003-4819-158-4-201302190-00009. [DOI] [PubMed] [Google Scholar]
  • 30.William W.N., Jr., Zhang J., Zhao X., et al. Spatial PD-L1, immune-cell microenvironment, and genomic copy-number alteration patterns and drivers of invasive-disease transition in prospective oral precancer cohort. Cancer. 2023 doi: 10.1002/cncr.34607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Xu S.B., Wang M.Y., Shi X.Z., et al. Influence of PD-1/PD-L1 on immune microenvironment in oral leukoplakia and oral squamous cell carcinoma. Oral Dis. 2022;10 doi: 10.1111/odi.14332. [DOI] [PubMed] [Google Scholar]
  • 32.Yagyuu T., Funayama N., Imada M., Kirita T. Effect of smoking status and programmed death-ligand 1 expression on the microenvironment and malignant transformation of oral leukoplakia: a retrospective cohort study. PLoS One. 2021;16(4) doi: 10.1371/journal.pone.0250359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Ries J., Agaimy A., Wehrhan F., et al. Importance of the PD-1/PD-L1 axis for malignant transformation and risk assessment of oral leukoplakia. Biomedicines. 2021;9(2) doi: 10.3390/biomedicines9020194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Yagyuu T., Hatakeyama K., Imada M., et al. Programmed death ligand 1 (PD-L1) expression and tumour microenvironment: Implications for patients with oral precancerous lesions. Oral Oncol. 2017;68:36–43. doi: 10.1016/j.oraloncology.2017.03.006. [DOI] [PubMed] [Google Scholar]
  • 35.Ioannidis J.P., Patsopoulos N.A., Rothstein H.R. Reasons or excuses for avoiding meta-analysis in forest plots. BMJ. 2008;336(7658):1413–1415. doi: 10.1136/bmj.a117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Monteiro L., Mariano L.C., Warnakulasuriya S. Podoplanin could be a predictive biomarker of the risk of patients with oral leukoplakia to develop oral cancer: a systematic review and meta-analysis. Oral Dis. 2022 doi: 10.1111/odi.14378. [DOI] [PubMed] [Google Scholar]
  • 37.Mello F.W., Melo G., Guerra E.N.S., Warnakulasuriya S., Garnis C., Rivero E.R.C. Oral potentially malignant disorders: a scoping review of prognostic biomarkers. Crit Rev Oncol Hematol. 2020;153 doi: 10.1016/j.critrevonc.2020.102986. [DOI] [PubMed] [Google Scholar]
  • 38.Ramos-Garcia P., Gonzalez-Moles M.A., Warnakulasuriya S. Significance of p53 overexpression in the prediction of the malignant transformation risk of oral potentially malignant disorders: a systematic review and meta-analysis. Oral Oncol. 2022;126 doi: 10.1016/j.oraloncology.2022.105734. [DOI] [PubMed] [Google Scholar]
  • 39.Monteiro L., do Amaral B., Delgado L., et al. Podoplanin expression independently and jointly with oral epithelial dysplasia grade acts as a potential biomarker of malignant transformation in oral leukoplakia. Biomolecules. 2022;12(5) doi: 10.3390/biom12050606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Kujan O., van Schaijik B., Farah C.S. Immune checkpoint inhibitors in oral cavity squamous cell carcinoma and oral potentially malignant disorders: a systematic review. Cancers (Basel) 2020;12(7) doi: 10.3390/cancers12071937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Elmusrati A., Wang J., Wang C.Y. Tumor microenvironment and immune evasion in head and neck squamous cell carcinoma. Int J Oral Sci. 2021;13(1):24. doi: 10.1038/s41368-021-00131-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Stasikowska-Kanicka O., Wagrowska-Danilewicz M., Danilewicz M. CD8+ and CD163+ infiltrating cells and PD-L1 immunoexpression in oral leukoplakia and oral carcinoma. APMIS. 2018;126(9):732–738. doi: 10.1111/apm.12881. [DOI] [PubMed] [Google Scholar]
  • 43.Cai X., Zhang J., Peng Y., et al. The preliminary exploration of immune microenvironment in oral leukoplakia concomitant with oral submucosal fibrosis: a comparative immunohistochemical study. J Oral Pathol Med. 2023;52(7):666–672. doi: 10.1111/jop.13434. [DOI] [PubMed] [Google Scholar]
  • 44.Yang J.Y., Wang F., Zhou G. Characterization and function of circulating mucosal-associated invariant T cells and γδT cells in oral lichen planus. J Oral Pathol Med. 2022;51(1):74–85. doi: 10.1111/jop.13250. [DOI] [PubMed] [Google Scholar]
  • 45.Ray J.G., Chatterjee R., Chaudhuri K. Oral submucous fibrosis: a global challenge. Rising incidence, risk factors, management, and research priorities. Periodontol 2000. 2019;80(1):200–212. doi: 10.1111/prd.12277. [DOI] [PubMed] [Google Scholar]
  • 46.William W.N., Jr., Zhao X., Bianchi J.J., et al. Immune evasion in HPV(-) head and neck precancer-cancer transition is driven by an aneuploid switch involving chromosome 9p loss. Proc Natl Acad Sci U S A. 2021;118(19) doi: 10.1073/pnas.2022655118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Hanna G.J., Villa A., Nandi S.P., et al. Nivolumab for patients with high-risk oral leukoplakia: a nonrandomized controlled trial. JAMA Oncol. 2024;10(1):32–41. doi: 10.1001/jamaoncol.2023.4853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Cai X., Zhang J., Li L., et al. Copy number alterations predict development of OSCC from oral leukoplakia. J Dent Res. 2024;103(2):138–146. doi: 10.1177/00220345231217160. [DOI] [PubMed] [Google Scholar]
  • 49.Leshchiner I., Mroz E.A., Cha J., et al. Inferring early genetic progression in cancers with unobtainable premalignant disease. Nat Cancer. 2023;4(4):550–563. doi: 10.1038/s43018-023-00533-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Wils L.J., Poell J.B., Brink A., et al. Elucidating the genetic landscape of oral leukoplakia to predict malignant transformation. Clin Cancer Res. 2023;29(3):602–613. doi: 10.1158/1078-0432.CCR-22-2210. [DOI] [PubMed] [Google Scholar]
  • 51.Cai X., Peng C., Cui Y., et al. Identification of genomic alteration and prognosis using pathomics-based artificial intelligence in oral leukoplakia and head and neck squamous cell carcinoma: a multicenter experimental study. Int J Surg (Lond Engl) 2025;111(1):426–438. doi: 10.1097/JS9.0000000000002077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Gurizzan C., Lorini L., Paderno A., et al. Immunotherapy for the prevention of high-risk oral disorders malignant transformation: the IMPEDE trial. Bmc Cancer. 2021;21(1):561. doi: 10.1186/s12885-021-08297-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

mmc1.docx (24.5KB, docx)

Articles from International Dental Journal are provided here courtesy of Elsevier

RESOURCES