Prognostic value of risk factors in Oral Potentially Malignant disorders and Oral Squamous Cell Carcinoma: an Umbrella Review

doi:10.21203/rs.3.rs-8408776/v1

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Systematic Review

Prognostic value of risk factors in Oral Potentially Malignant disorders and Oral Squamous Cell Carcinoma: an Umbrella Review

https://doi.org/10.21203/rs.3.rs-8408776/v1

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Background

Oral Squamous Cell Carcinoma ranks the 7th most common cancer worldwide. Numerous systematic reviews and meta-analyses have been published over the past decade with many identified risk factors. This Umbrella aims to synthesize from the body of available evidence, which features of oral potentially malignant disorders (OPMDs) most contribute to malignant transformation, while reporting risk prognostic/prediction models and methodological gaps.

Methods

This umbrella review followed the PRISMA 2020 checklist and was registered with PROSPERO (CRD42024584847). A Comprehensive search of PubMed, Scopus, and Web of Science (up to February 2025) was done to identify systematic reviews and meta-analyses evaluating risk and prognostic factors in OPMDs and OSCC. Screening was done by two independent reviewers. Eligible studies were appraised using AMSTAR-2, with data synthesized descriptively.

Results

Ten systematic reviews and meta-analyses published between 2019 and 2024 were included, encompassing diverse populations and study designs. Frequently assessed prognostic factors included age, sex, tobacco and alcohol use, lesion site, histopathological grade, and molecular markers such as podoplanin, ALDH1A1, PROM1, and cancer stem cell–related biomarkers. Pooled malignant transformation rates varied across lesion types—1.16% for oral lichen planus and up to 19.9% for Erythroplakia. Strong associations were found between tobacco exposure and oral cancer risk (OR up to 15.3). Biomarkers like podoplanin and ALDH1A1 exhibited significant prognostic potential (HR: 2.9–8.9).

Conclusion

This umbrella review underscores that both molecular and clinical parameters, especially epithelial dysplasia, lesion site, tobacco exposure, and biomarkers that hold prognostic value for malignant transformation in OPMDs and survival in OSCC. Future research should prioritize standardized biomarker validation, multicentric prospective designs, and integrated prognostic models to improve personalized risk prediction and management.

Dentistry

Cancer Biology

Oral Squamous Carcinoma

Oral Potentially Malignant Disorders

Prognosis

Risk Factors

Umbrella Review

Oral squamous cell carcinoma (OSCC) remains a significant public health challenge, with an increasing number of cases and deaths globally [1]. According to the 2022 GLOBOCAN (Global Cancer Observatory) report, oral squamous cell carcinoma (OSCC) ranks as the seventh most common cancer globally, with an estimated 377,700 new cases and 177,800 deaths reported in 2020, with a disproportionately high burden in low and middle-income countries, particularly in the Asia region [1, 2]. OSCC incidence is projected to increase by up to 40% by 2040 [2].

Although OSCC develops from the interplay of multiple factors, its development is commonly associated with tobacco use, betel nut chewing, alcohol consumption, nutritional deficiencies, poor oral hygiene, chronic traumatic dental injuries, and viral infections such as human papillomaviruses (HPVs) [1, 3]. Therefore, the high prevalence of OSCC and its multifactorial aetiology underscore the need for a robust and comprehensive prognostic indicator, which can enhance early detection strategies, improve survival rates, and ultimately enhance quality of life in the long term.

Patients with OSCC do not all experience the same results; i.e., survival rates and quality of care differ between countries, regions, and even healthcare facilities. For example, a study in Uganda showed that only about 20.7% of patients survive 5 years after diagnosis, and almost half of them die within just 2 years [4]. At the same time, patients (with stage III OSCC) in Taiwan (a resource-rich country) experienced a survival rate of 26.6% after 5 years [4]. Additionally, a study from Chongqing Medical University in China reported a significant five-year survival rate of 59.3% among patients [5]. These differences may be due to variations in early detection, access to treatment, socioeconomic status, or variations in risk factors like tobacco and alcohol use.

Additionally, a considerable number of oral squamous cell carcinomas (OSCCs) develop from oral potentially malignant disorders (OPMDs) [6, 7], including leukoplakia, Erythroplakia, oral lichen planus, and oral submucous fibrosis [7, 8]. However, not all OPMDs share the same risk of malignant transformation; for example, erythroplakia has a very high rate of malignant transformation (up to 50% in some studies). Oral lichen planus typically carries a lower risk, although it is still higher than that of normal mucosa [9]. This different prognostic pattern is based on lesion type, severity of dysplasia, and patient-related factors like tobacco or alcohol use [6, 7, 9]. Therefore, this difference makes it essential to refine risk prediction and modify surveillance or intervention strategies as appropriate.

Several studies have examined these risk factors in isolation, and it has become increasingly important to bring them all together to provide a clearer picture. For example, even though individual studies sometimes describe the risk of OPMDs turning into cancer as “low to moderate”, pooled analyses show a significant overall risk (≈ 8%) when lesions are followed over an extended period of time, with markedly higher risks in specific types and subtypes [10]. Erythroplakia, in particular, carries a very high malignant potential, and histology at presentation frequently reveals significant dysplasia or carcinoma in situ [10, 11]. Additionally, definitions, nomenclature, and grading have evolved, including a recent WHO Collaborating Centre consensus that standardizes the terminology of OPMD. This is important because terminology consistency is a prerequisite for comparing prognostic signals across studies [12].

For established OSCC, the overall framework for determining and understanding prognosis has also shifted with the 8th edition of the American Joint Committee on Cancer (AJCC) staging system [13]. Two changes stand out: the incorporation of depth of invasion (DOI) into the T classification, and the refinement of nodal staging to account for extranodal (extra capsular) extension. Studies have shown that these characteristics have a direct impact on patient outcomes [13]. Despite these improvements, staging is not 100% accurate in predicting outcomes, and patient-level differences, such as age, comorbidity, exposures (including tobacco, alcohol, and areca/betel quid), and treatment factors, introduce different and inconsistent outcomes when comparing groups of patients [14].

Therefore, this leads us to ask: Which features of OPMDs most reliably predict malignant transformation? When OSCC is diagnosed, which factors, alone or in combination, best predict survival and recurrence, and how do they interact with today’s standard of treatment? These are questions clinicians and researchers will have to find answers to.

It is also worth mentioning that researchers are developing tools to predict risks and outcomes in patients; however, these tools do not always perform consistently when tested in different settings, and their usefulness in real-world patient care remains unreliable [1, 15]. In light of the complexity of this field, a single systematic review is often too narrow to capture the full scope of evidence. Research on OPMDs and OSCC prognosis often spans diverse populations, evaluates multiple clinical outcomes, and investigates a wide range of prognostic markers, including clinical features, histopathologic alterations, molecular changes, and behavioural risk factors. Numerous systematic reviews and meta-analyses have been published over the past decade, many of which overlap, resulting in scattered and occasionally inconsistent conclusions.

An umbrella review offers a solution. By collating, evaluating, and comparing the highest levels of synthesized evidence, umbrella reviews can map the strength, consistency, and credibility of associations across diverse risk factors, highlight where conclusions converge or conflict, and isolate unclear areas and warrant primary research [16, 17]. Applied to OPMDs and OSCC, this approach can (i) benchmark malignant transformation risks across OPMD entities and phenotypes; (ii) grade the prognostic weight of clinicopathologic features in OSCC (e.g., depth of invasion-DOI as continuous vs categorical, nodal burden, extra nodal extension, margin status, perineural/lymphovascular invasion); and (iii) clarify how patient-level exposures (tobacco, alcohol, areca/betel quid) and demographic factors modulate prognosis in real-world settings. [10, 11, 13].

This umbrella review, therefore, aims to collect and grade the best available evidence on risk factors in both OPMDs and OSCC. It also aims to identify which features predict cancer transformation, which factors predict survival and recurrence, and how strong the evidence is, with the hope that it gives clinicians a practical guide for patient care.

Prospero registration

The umbrella review was registered in PROEPERO (CRD42024584847) on October 17, 2024. Furthermore, an umbrella review was conducted in accordance with the PRISMA-overview for systematic reviews and meta-analyses checklist [18] (Supplementary file).

2.1: Search strategy and Search information

The combination of keyword and/or free text was utilized to find relevant reviews: ‘oral precancer’, ‘oral squamous cell carcinoma’, ‘risk factor/risk assessment/risk’, and ‘prognosis/survival’. Detail search strategy is provided in Appendix I. No filters were used while searching in the databases. PubMed, Scopus, and Web of Science were searched. Potential reviews were identified and exported. In addition, manual search was conducted to identify additional reviews.

2.2: Screening and Selection

Identified reviews were imported into the Rayyan. AI web application [19]. Two authors independently screened the article first by reading the title, abstract, and keywords. After removing non-eligible reviews in this step, Full-text articles were retrieved and screened further for final eligibility. Cross-references were searched to identify additional systematic reviews. Any disagreements regarding the eligibility of studies were resolved by consulting a third author.

2.3:Eligibility criteria

Selection and inclusion in review was carried as per following inclusion and exclusion criteria:

Inclusion criteria:

Systematic reviews with or without meta-analysis of randomized, non-randomized observational/ interventional studies

Systematic reviews assessing association between risk factors and prognosis in OPMD and OSCC.

Systematic reviews correlating risk factors with incidence, survival or death, recurrence after treatment or metastasis (in OSCC).

Systematic reviews providing follow-up and other relevant outcomes from the included studies (if applicable).

Studies reporting the pooled effect size (OR, RR, HR, Cohen’s d) for the specific risk factor and duration of follow-up and other relevant data items.

Exclusion criteria:

Systematic reviews with no defined research question or not relevant research question.

Systematic review protocols

Narrative reviews or scoping review

2.4: Data extraction

The relevant data was extracted from full-text articles. Two reviewers extracted the following data 1. Characteristics of each systematic review (SR) including the authors, date of publication, country of origin, aim of the SR, research or focus question, and the PICOS framework, 2. Participant details such as population characteristics including ethnicity or race, number of participants, gender, age, site of disease, associated risk factors and their measurement, TNM staging, recurrence, metastasis, follow-up duration, treatment modalities, and types of outcomes assessed. In addition, PROSPERO registration number, duration of search, search strategies and filters applied, number of databases searched, types of studies included, and the ratio of randomized controlled trials (RCTs) to observational studies. The data extraction method, along with a list of excluded studies and the reasons for exclusion, funding sources or sponsorships and any declared conflicts of interest were also recorded. Information about reported pooled effect sizes with 95% confidence intervals (odds ratios, risk ratios, hazard ratios, or log hazard ratios), Survival analyses (overall survival, disease-free or recurrence-free survival, and progression-free survival), method of survival analysis, risk of bias and quality assessments tools used in SR were extracted.

Reviewers also extracted statistical analyses that were applied, including the methods used for summary synthesis, statistical tests applied, type of meta-analysis (if applicable), subgroup analyses, heterogeneity percentages (I² coefficient), and assessments of publication bias. Limitations of each systematic review were also noted. Any disagreements regarding the extraction of quantitative data were resolved by consulting a third author. If necessary, additional data or clarification were sought from the original authors of the systematic reviews.

Summary Synthesis and Critical Quality Assessment

The characteristics of included SRs were summarized descriptively. Meta-analysis was planned based on availability of the homogenous data. However, outcome reporting was heterogenous, hence, no meta-analysis was carried out. A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) was used to critically appraise the included SRs and MAs [20].

3.1:Included studies

A total of 10 systematic reviews and meta-analyses were included after applying eligibility criteria [21–30] (Fig. 1). These studies collectively synthesized evidence on risk factors associated with OPMDs and prognostic determinants in OSCC (Table 1). Systematic Reviews (Mata-analysis) were published between 2019 and 2024, originating from diverse regions including Spain, India, Chile, and Portugal, with frequent contributions from European and South Asian institutions. Notably, several studies originated from high-impact journals such as Oral Oncology, Cancers, and Oral Diseases, reflecting strong research interest in the topic.

3.2: Pre-registration and Funding

Across the included reviews, most were both systematic reviews and meta-analyses, though a few were purely systematic in nature. A significant number of studies reported PROSPERO registration, reflecting methodological transparency and adherence to best practices in evidence synthesis. Funding sources were variably declared; while many SRs conducted without funding support, a few received government or institutional support, especially from Health departments and Research councils. Keim-del Pino et al. (2024) from Spain, published in Cancers, conducted a systematic review and meta-analysis registered with PROSPERO CRD42024511457, without external funding [28]. Dwivedi et al. (2024) from India, published in the Asian Pacific Journal of Cancer Prevention, received financial support from the Department of Health Research, Ministry of Health & Family Welfare, and registered the review under PROSPERO CRD42021282787 [24]. Rivera et al. (2020) from Chile, in Molecular and Clinical Oncology, conducted a systematic review without declared funding and registered it under PROSPERO CRD42018086476 [26]. González-Moles et al. (2020) from Spain, publishing in Oral Oncology, also declared no funding and mentioned PROSPERO registration, although without number [30]. Similarly, Lorenzo-Pouso et al. (2022) from Spain, in the Journal of Oral Pathology & Medicine, reported no funding and was registered with PROSPERO CRD42022299026 [21]. An earlier review by González-Moles et al. (2019) in Oral Oncology also noted no funding and was registered under PROSPERO CRD42019128539 [23]. Monteiro et al. (2020) from Portugal, publishing in Oral Diseases, declared partial funding from Henry Schein Cares and CAPES-FAPESC, with PROSPERO registration number CRD42020163464, while their later review in 2022 in the same journal reported no funding and was registered under CRD42022329326 [29]. Another study by González-Moles et al. (2021) in Cancers was funded by the Plan Andaluz de Investigación and registered under PROSPERO CRD42021267896 [22]. Finally, Saluja et al. (2019) from India, in Cancer Epidemiology, Biomarkers & Prevention, received funding from the Department of Health Research, India, though PROSPERO registration was not reported [27]. This diversity in authorship, geography, funding, and transparency contributes to a broad and balanced representation of the current evidence landscape regarding risk and prognosis in OPMDs and OSCC.

3.3:Type of studies Included in SR/MA

The included SRMA demonstrated a wide range of scope and methodological diversity in terms of review types, number of primary studies, and study designs. Keim-del Pino et al. conducted a combined SRMA including 110 observational studies, making it one of the most comprehensive in terms of study volume [28]. Dwivedi et al. also performed both a SRMA, incorporating 49 studies, of which 40 were case-control, 7 cross-sectional, and 2 cohort studies [24]; however, it should be noted that not all included studies focused solely on oral cancer or OPMDs, as the review encompassed various cancer types. Rivera et al. carried out a systematic review limited to 4 retrospective cohort studies [26]. González-Moles et al. contributed multiple reviews: one included 27 studies without a detailed report on study design; another review included 82 studies, of which 74 were retrospective longitudinal and 8 were prospective longitudinal studies; and yet another review analyzed 23 studies qualitatively and 21 quantitatively, primarily comprising retrospective longitudinal studies with a single prospective longitudinal study [22, 23, 30]. Lorenzo-Pouso et al. conducted both a systematic review and meta-analysis that synthesized 10 longitudinal observational studies [21]. Monteiro et al. also conducted two reviews: the first was a systematic review involving 46 studies, primarily retrospective cohort studies (n = 38), along with 6 randomized clinical trials (RCTs), 1 prospective cohort study, and 1 quasi-experimental study [25]. The second review, a combined systematic review and meta-analysis, included 6 studies, comprising 5 retrospective cohort studies and 1 randomized clinical trial [29]. Lastly, Saluja et al. included 18 studies, mostly retrospective in nature, in their SRMA [27]. Most SRs have a predominance of retrospective observational studies with relatively fewer high-quality prospective studies and RCTs.

3.4: Population and Lesions

Sample size

The included systematic reviews and meta-analyses encompassed diverse populations, primarily focusing on patients with OPMDs and OSCC, with notable variability in follow-up durations and language restrictions. Keim-del Pino et al. examined only OLP cases and did not specify the follow-up period; notably, they did not restrict their review to English-language publications [28]. In contrast, Dwivedi et al. included both OSCC and OPMD populations but applied language restrictions, excluding non-English articles, though follow-up duration was not detailed [24].

Rivera et al. studied OPMD cases, including oral dysplasia, leukoplakia, and erythroplakia, with English-only inclusion, and did not report follow-up duration [26]. González-Moles et al. included both OLP and OSCC cases, reporting a wide range of follow-up durations from 10 days to 660 months, and applied language restrictions [22]. In another review, Lorenzo-Pouso et al. focused on oral erythroplakia, with a reported mean follow-up of 6.66 years (range 3.83–16 years), also limited to English-language studies [21]. A further review by González-Moles et al. on various OPMDs, including OLP, oral lichenoid lesions, lichenoid reactions, and dysplastic OLP, provided a detailed distribution of follow-up durations across studies: 29 studies with ≥ 6 months, 53 with < 6 months, 16 with ≥ 12 months, and 66 with < 12 months, all with English-language restrictions [23]. Monteiro et al. (Monteiro L et al. 2020; 2022) authored two reviews centered exclusively on oral leukoplakia [25, 29]. One review (Monteiro L et al. 2020) did not report follow-up duration [25], while the other (Monteiro L et al. 2022) included studies with follow-up periods ranging from 32 to 90 months [29]; both were restricted to English-language studies [25, 29]. In contrast, one review by González-Moles et al. that analyzed both OSCC and OPMD (specifically proliferative verrucous leukoplakia - PVL) reported a mean follow-up of 65.63 months and was among the few reviews that did not impose language restrictions [23]. Lastly, Saluja et al. evaluated various OPMDs such as OLP, oral leukoplakia, and oral erythroplakia, with reported follow-up ranging from 0.66 years to 16 years, and applied English-only inclusion criteria. Overall, most reviews focused on OPMD populations, particularly OLP and oral leukoplakia, with considerable variation in follow-up duration and a prevalent

3.5: Prognostic Risk Factors Assessed

Across the included systematic reviews and meta-analyses, a different prognostic risk factors were investigated for their potential role in predicting malignant transformation of OPMDs and prognosis in OSCC. The spectrum of risk factors spanned molecular biomarkers, clinical characteristics, lifestyle habits, and histopathological features. Keim-del Pino et al. explored an extensive panel of 104 biomarkers associated with cancer hallmarks, assessing their expression in OLP using immunohistochemistry techniques [28]. The comparator groups included both healthy individuals and patients diagnosed with OSCC, providing a contrast to identify specific biomarkers that may predict progression. Dwivedi et al. focused on non-tobacco product (NTP) usage—including betel quid, areca nut, and paan—as risk factors [24]. They defined NTP exposure clearly and compared outcomes between exposed and unexposed groups across both case-control and cohort designs, though the scope extended beyond OSCC and OPMD to other cancer sites [24]. Rivera et al. assessed key prognostic biomarkers such as the degree of dysplasia, expression of retinal aldehyde dehydrogenase 1 (ALDH1A1), prominin-1 (PROM1), and podoplanin (PDPN) [26]. These biomarkers were evaluated using logistic regression or Cox proportional hazard models, with comparator groups based on absence of dysplasia or negative biomarker expression [26]. Several studies by González-Moles et al. investigated traditional clinical risk factors, including age, sex, tobacco use, and alcohol consumption [22, 23, 28]. These factors were evaluated by stratifying the populations into groups such as smokers vs. non-smokers, males vs. females, and age groups above or below 40 years. Another study by the same group focused on the malignant transformation rate (MTR) of OLP and proliferative verrucous leukoplakia (PVL), without comparator groups but using transformation rates to assess prognostic implications [23].

Lorenzo-Pouso et al. evaluated the impact of tobacco, betel quid, alcohol consumption, and epithelial dysplasia in patients diagnosed with oral erythroplakia (OE), identifying their prognostic relevance by comparing patients with and without these exposures [21]. Monteiro et al. conducted two reviews concentrating on tissue-based biomarkers in patients with oral leukoplakia [25, 29]. In their broader review, they comprehensively assessed over 40 molecular markers, including p53, Ki-67, CD133, EGFR, SOX2, Nanog, and microRNAs, among others [25]. The association of these biomarkers with cancer incidence was evaluated using immunohistochemistry, gene expression analysis, and loss of heterozygosity (LOH) studies [25]. In a more focused review, they reported on podoplanin expression as a potential indicator of malignant progression [29]. Saluja et al. reviewed biomarkers associated with cancer stem cell–like characteristics (CSCs), which are hypothesized to play a critical role in tumor initiation, resistance, and progression [27]. The markers included CD133, CD44, CD24, OCT4, SOX2, NANOG, ALDH1, and ABCG2, which were identified via specific expression patterns distinguishing CSCs from other tumor populations [27].

Overall, the umbrella review reveals a complex interplay of clinical and molecular factors that hold potential prognostic value in assessing the malignant transformation risk of OPMDs and the progression of OSCC. The diversity in measurement methods, comparator groups, and study designs highlights the need for standardized biomarker validation and longitudinal follow-up to strengthen prognostic precision in clinical practice.

3.6: Outcomes Evaluated

The included reviews encompassed a range of prognostic and clinical outcomes across the included systematic reviews and meta-analyses. The primary outcomes most frequently assessed were malignant transformation of OPMDs into OSCC, along with overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and recurrence rates [24, 27, 30]. Secondary outcomes included treatment response, disease progression, and the impact of conventional and molecular risk factors on prognosis.

Several reviews focused on specific prognostic indicators, such as the expression of cancer hallmarks in OLP and the differential expression of proteins detected via immunohistochemistry (IHC) [22, 23, 25]. These analyses sought to uncover early oncogenic molecular mechanisms driving malignant transformation in OLP, with the goal of identifying preventive or predictive biomarkers.

In studies evaluating transformation, a key emphasis was placed on histological outcomes such as the progression from epithelial dysplasia to invasive SCC, including the prevalence and grade of dysplastic changes (low-grade, high-grade, or absent) [25, 26, 30].

Meta-analyses specifically focusing on OLP-OSCC evaluated mortality rates, tumor staging (T1/T2, N+), histological grade, and clinical staging (I/II), and compared these with conventional OSCC cases lacking OLP history [22, 23, 28]. Covariates such as age, sex, tobacco and alcohol use, tumor location, and multiple tumor development were commonly assessed for their impact on patient prognosis.

Moreover, several reviews targeted molecular markers such as podoplanin and cancer stem cell (CSC) markers, analyzing their utility in predicting malignant transformation and distinguishing between indolent and high-risk lesions [29, 30]. These studies concluded that evaluating a panel of CSC markers—rather than relying on single-marker analysis—was more effective in stratifying progression risk in patients with OPMDs like oral leukoplakia and epithelial dysplasia.

Overall, the outcomes explored in the reviews reinforce the need for integrative prognostic models that combine clinical features, histological grading, and biomarker profiles to better predict malignant transformation and improve survival outcomes in OPMD and OSCC patients.

3.7: Summary Synthesis of Effect Measures and Statistical Outcomes

Across the included systematic reviews and meta-analyses, a diverse set of prognostic outcomes and effect estimates were reported. Various statistical measures, including odds ratios (OR), hazard ratios (HR), relative risks (RR), and pooled proportions (PP), were used to evaluate associations between clinical, lifestyle, histopathological, and molecular risk factors with malignant transformation, survival, and recurrence in OPMDs and OSCC.

Dwivedi et al. reported strong associations between tobacco exposure and the development of oral cancer (OR = 5) as well as OPMDs (OR = 15.3), both with statistical significance (p < 0.01) and high heterogeneity (I² > 80%) [24]. Rivera et al. evaluated cancer stem cell (CSC) markers, identifying ALDH1A1 and PROM1 as significantly associated with malignant transformation, with HRs ranging from 2.9 to 8.9 [26]. Saluja et al. found CSC marker expression in OPMDs to be predictive of increased OSCC risk, reporting a pooled RR of 3.31, with CD133 showing the highest individual risk (RR = 4.20) [27].

Multiple pooled analyses by González-Moles et al. revealed a global malignant transformation rate of 1.16% in oral lichen planus (OLP), with considerable heterogeneity (I² = 72.97%, p < 0.001) [22, 23]. Prognostic variables such as tobacco use, alcohol consumption, lesion site (e.g., tongue), histopathological grade, and method of diagnosis were consistently associated with increased malignant risk. Lorenzo-Pouso et al. quantified the pooled malignant development rate in oral erythroplakia at 19.9% (95% CI: 1.6–41.4), with very high heterogeneity (I² = 91.74%) [21].

Monteiro et al. evaluated tissue molecular biomarkers in oral leukoplakia and reported a pooled HR of 3.72 (95% CI: 2.40–5.76) for malignant transformation, with no observed heterogeneity (I² = 0%), indicating a highly consistent effect across included studies [25]. Other included studies also explored secondary outcomes such as disease progression and recurrence; however, these were variably reported and not uniformly defined across reviews.

Subgroup analyses, where performed, revealed additional insights into the impact of variables like lesion site, sex, age, and concurrent risk habits (e.g., alcohol and tobacco). Only 4 studies performed sensitivity analysis. Sensitivity analyses confirmed the robustness of findings in reviews by González-Moles et al. and Saluja et al., with no significant alteration of outcomes after excluding low-quality or high-bias studies [22, 27]. Overall, the evidence across reviews emphasizes the significant prognostic value of both molecular markers (e.g., CSC, podoplanin) and clinical parameters (e.g., dysplasia grade, tobacco use, lesion location) in determining malignant transformation and survival outcomes in OPMDs and OSCC.

4.1 Quality Assessment

Most included reviews used validated tools such as QUIPS (Quality In Prognosis Studies tool.), REMARK (REporting recommendations for tumor MARKer prognostic studies), Joanna Briggs Institute, and the Newcastle-Ottawa Scale to assess methodological quality. A large proportion of primary studies demonstrated moderate to high risk of bias, especially in domains related to study confounding, prognostic factor measurement, and statistical analysis and reporting, while only a few showed consistently low risk across all areas. Publication bias was assessed in most reviews using funnel plots and Egger’s tests, with no significant bias detected in key reviews by Keim-del Pino et al. [28], Dwivedi et al. [24], and González-Moles et al. [22], though some studies did not perform this assessment. REMARK-based evaluations generally reflected high reporting quality, albeit with notable omissions like sample size justification and missing data handling. Joanna Briggs-based assessments revealed variable methodological rigor, especially concerning sampling strategies and subgroup classifications.

The systematic reviews and meta-analyses collectively highlight the potential prognostic value of certain biomarkers—particularly podoplanin, LOH, and cancer stem cell markers—in predicting malignant transformation in OPMDs, including OLP, leukoplakia, and proliferative verrucous leukoplakia (PVL) [21–30]. Several studies found significant associations between these biomarkers and increased cancer risk, especially in cases with specific clinical features like erosive or atrophic lesions, tongue localization, and risk habits such as tobacco or alcohol use [22–25, 30]. However, widespread clinical implementation is hindered by substantial limitations, such as small sample sizes, lack of standardized diagnostic and reporting criteria, absence of individual participant data, inadequate follow-up durations, and high heterogeneity across studies. These limitations underscore the need for future high-quality, longitudinal studies with larger, well-defined cohorts, standardized methodologies, and detailed stratified data reporting to validate the biomarkers’ clinical utility and enhance risk stratification in OPMDs.

4.2 Quality Assessment of Included SR (AMSTAR 2)

Out of 10, 7 critically low, 1 low, 2 moderate level of quality based on AMSTAR2 assessment criteria (Appendix II). Most of included SR did not provided information regarding source of funding in the primary studies

Our umbrella review of ten systematic reviews provides a comprehensive assessment of the prognostic values of risk factors, especially those linked to OPMDs in the development of OSCC. In our review, Dwivedi et al reported a strong association between tobacco exposure and the development of oral cancer as well as OPMDs [24]. This finding was also supported by a study conducted by Shaikh et al., which revealed a significant association between the use of smokeless tobacco and OPMDs [31]. Alcohol was also noted as one of the variables with an impact on the transformation of OPMD to OSCC, which Almadan et al (2025 highlighted as one of the risk factors for OSCC [32].

Age was found in the index study to be a prognostic factor, although the specific effect was not clearly outlined. However, Almadeen et al. (2025) found in their study that OSCC affected the elderly and males more than the young and females, respectively [32]. Our findings on the depth of invasion were echoed by Kim et al. (2024), who noted that depth of invasion is a prognostic factor, serving as a marker for obtaining prognostic indices for OSCC [33]. The location of the lesion within the mouth was noted to influence the risk of Malignant transformation, possibly. However, this is not an independent determinant and is undoubtedly related to the etiological factors. This finding on the location of the lesion and the development of Malignancy, made by Syed Ali Khurram in the United Kingdom, corroborates our findings that the lesion site can prognosticate the development of OSCC. Lorini et al also supported this in their study, stating that Patients were primarily affected by OPMDs located on the tongue (43.3%) [34].

PCNA and p21 were identified as promising predictive markers for evaluating the risk of malignant transformation of OLP; however, they require further validation. The focus of future research on validation of predictive biomarkers of OLP should be considered as a high priority because it will accelerate the introduction of newly discovered markers into the clinical setting [35], this was done by Keim-del Pino et al in our index study who explored an extensive panel of 104 biomarkers associated with cancer hallmarks, assessing their expression in OLP using immunohistochemistry techniques [28].

A retrospective study was conducted by Herrera CF et al on 27 cases of OLP and 30 cases of OSCC [36]. Clinical data were obtained from medical records, and all cases were classified as mild, moderate, and severe for OLP, and well-differentiated, moderately differentiated, or poorly differentiated for OSCC cases [36]. The expression of ALDH1A1 and ALDH2 in OLP and OSCC was evaluated using the immunohistochemical technique [36]. The male sex was predominant in both OLP and OSCC cases [36]. The oral tongue was the most affected site in both groups. OLP showed positive protein expression of ALDH1A1 in all cases, both basal and suprabasal epithelial layers, whereas ALDH2 showed less protein expression [36]. In OSCC, the immunohistochemical reaction for ALDH1A1 expression was positive in 70% of cases, whereas ALDH2 expression was positive in all cases [36]. This study demonstrated the gradual loss of ALDH1A1 expression in OSCC in comparison with OLP, and the increased ALDH2 expression in OSCC [36]. This further solidified claims that sex and location of potentially malignant lesion had a role in prognosis in oral potentially malignant disorders and Oral Squamous Cell Carcinoma [36]; however disparity arose with findings on ALDH1 which was discovered by Saluja et al [37] to play a critical role in tumor initiation, resistance and progression but was seen to be negative in the study done by Herrera.

A meta-analysis by Khodadadi et al. (2025) on the malignant transformation rate of oral precancerous disorders to oral cancer showed an elevated risk of Oral cancers associated with overall Oral Potentially Malignant disorders (OR = 2.5, 95% CI 2.43–2.58) [37]. The highest risk of OC in OPMDs were Leukoplakia (SOR = 3.35 (95% CI 3.21–3.50), Erythroplakia (SOR = 3.3 (95% CI 3.21–3.50), oral epithelial dysplasia (SOR = 1.41 (95% CI 1.20–1.73), and oral Submucosa fibrosis (SOR = 2.9 (95% CI 2.70–3.12) [37]. Oral Leukoplakia is the most common potentially malignant lesion of the oral cavity, with a prevalence of 2%–3% of the global population; it is more frequent in patients older than 40 years, and malignant transformation rates have been reported to range from 1% to 40%, with an average of 13% [38, 39, 40]. These studies suggest a significant association between OPMDs and OC; age and duration of follow-up may modify this association. Lorenzo-Pouso et al. in the index study quantified the pooled malignant development rate in oral erythroplakia at 19.9% (95% CI: 1.6–41.4), with very high heterogeneity (I² = 91.74%) [26].

Another marker that was discovered to be present in many oral squamous cell cancers in the umbrella review was podoplanin, a transmembrane glycoprotein receptor. In a study by Jannat et al, Podoplanin expression correlated significantly with OSCC histological grade, suggesting its potential as a prognostic marker [41]. High expression may indicate aggressive tumors and poorer outcomes, highlighting its relevance in evaluating and managing OSCC [41]. High expression may indicate aggressive tumors and poorer outcomes, highlighting its significance in assessing and managing OSCC.

Most of the studies recruited in this review were retrospective in nature; only a few were prospective. For studies examining the prognosis of risk factors in oral lesions, prospective studies should have been more numerous, as this would provide a better understanding of how exposure influences health outcomes in relation to OPMD and OSCC, and also help mitigate some bias that may have affected the results. Many of the studies lacked funding, but this did not significantly impact the overall quality of the studies.

Some of the strengths of this umbrella review include the use of a detailed methodological framework. All systematic reviews were conducted within five years (2019–2024), ensuring the inclusion of the most up-to-date evidence on oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC). Some of the limitations include variations in sample size, geographic coverage, population heterogeneity, and disparities in funding resources.

This umbrella review demonstrates strong methodological integrity and synthesizes a broad, contemporary evidence base linking molecular and clinical predictors with malignant transformation in OPMDs. Molecular biomarkers (e.g., podoplanin, ALDH1A1, cancer stem cell markers) and traditional clinical factors (e.g., dysplasia, lesion site, tobacco and alcohol exposure) are consistently associated with malignant transformation and disease progression. The findings have limitations such as heterogeneity in study design, limited prospective evidence, and variable biomarker validation, underscoring the need for more research. Future investigations should integrate molecular profiling with clinical variables to develop robust, evidence-based prognostic models that can guide early intervention and improve survival outcomes in oral oncology.

OSCC: Oral Squamous Cell Carcinoma
OPMDs: Oral Potentially Malignant Disorders
DOI: Depth Of Invasion
OR:Odds Ratio
RR: Relative Risk
HR: Hazard Ratio
CI: Confidence Interval
RCTs: Randomized Controlled Trials
SRMA: Systematic Reviews amd Meta-Analyses
OLP: Oral Lichen Planus
NTP: Nucleoside Triphosphate
PDPN: Podoplanin
ALDH1A1: Aldehyde Dehydrogenase 1 Family Member A1
PROM1: Prominin-1
MTR: Malignant Transformation
PVL: Proliferative Veruccous Leukoplakia
CD: Cluster of Differentiation
EGFR: Epidermal Growth Factor Receptor
SOX: SRY (Sex-determining Region Y)-box genes
Nanog: Nanog homeobox
MicroRNAs: Micro Ribonucleic Acids
ABCG: ATP-Binding Cassette Subfamily G
DFS: Disease-Free Survival
OS: Overall Survival
CSS: Cancer-Specific Survival
PP: Pooped Proportions
QUIPS: Quality In Prognosis Studies tool
REMARK: REporting recommendations for tumor MARKer prognostic studies
QUADAS-2: Quality Assessment of Diagnostic Accuracy Studies-2
DOR: Diagnostic Odds Ratio
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Ethics approval: Not applicable

Consent for publication: Not applicable

Clinical trial number: Not applicable

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests

Funding: No funding was received for this study

Author Contributions: All authors were involved in the writing, editing and drafting of this manuscript.

Acknowledgments: None

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Table 1 is available in the Supplementary Files section.

The authors declare no competing interests.

Table11.xlsx
Summary of Individual Study Characteristics
AppendixISearchStrategy2.docx
Search Strategy
AppendixIIAMSTAR21.xlsx
Scoring of systematic reviews or meta-analyses using AMSTAR 2

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Prognostic value of risk factors in Oral Potentially Malignant disorders and Oral Squamous Cell Carcinoma: an Umbrella Review

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Abstract

Background

Methods

Results

Conclusion

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1. Introduction

2. Methodology

2.1: Search strategy and Search information

2.2: Screening and Selection

2.3:Eligibility criteria

2.4: Data extraction

3. Results

3.1:Included studies

3.2: Pre-registration and Funding

3.3:Type of studies Included in SR/MA

3.4: Population and Lesions

3.5: Prognostic Risk Factors Assessed

3.6: Outcomes Evaluated

3.7: Summary Synthesis of Effect Measures and Statistical Outcomes

4.1 Quality Assessment

4.2 Quality Assessment of Included SR (AMSTAR 2)

4. Discussion

5. Conclusion

Abbreviations

Declarations

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Supplementary Files

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