Oral leukoplakia is a clinically distinct oral mucosal lesion that has a predominantly white appearance that cannot be rubbed off and cannot be clinically or pathologically attributed to any other diagnosable condition [1].  It is the most common potentially malignant disorder (PMD) of the oral cavity, carrying a variable but worrying risk of malignant transformation into oral squamous cell carcinoma (OSCC) [2]. The etiology of oral leukoplakia is multifactorial and therefore includes a variety of risk factors, including tobacco and smokeless tobacco use, betel quid chewing, alcohol use, and potentially genetic and epigenetic predispositions [3]. The prevalence of the lesion varies geographically based on cultural practices and environmental exposures, although more highly reported among populations with prevalent tobacco and betel quid use [4].

At histopathology, oral leukoplakia can range from simple hyperkeratosis and acanthosis to varying degrees of dysplasia and carcinoma in situ [5]. Such histologic features are utilized to assess the potential malignancy of the lesion [6]. In addition to these, molecular studies have shown diverse biomarkers and genetic changes that would potentially predict the risk of progression to OSCC, although their clinical usage remains strictly under intense investigation [7].

The clinical diagnosis and treatment of oral leukoplakia are extremely challenging due to its heterogeneity and unpredictable behavior [8]. Clinically, lesions are categorized based on their appearance into homogeneous and non-homogeneous types, where the latter type has a higher risk of malignant transformation [9]. Adjunctive diagnostic tools include toluidine blue staining, brush biopsies, and optical coherence tomography as a way to improve the detection of dysplastic or malignant changes, but routine use in clinical practice remains debated [10].

The approaches to management of oral leukoplakia are as varied as shown and range from conservative monitoring to surgical excision [11]. The choice to treat may be based on the size and location of the lesion, histological features, and patient-specific risk factors [12]. Therapeutic management with laser excision and cryotherapy aims to remove dysplastic tissue thereby reducing the chance of malignant transformation [1]. Beyond surgical therapeutic maneuvers, non-surgical therapeutic options such as chemopreventive agents and life style modifications have been studied, the effectiveness of which varies [3]. The recurrence of lesions after treatment and continued risk for malignancy even after therapy implicate long-term follow up and intensive surveillance [5].

Significant gaps in oral leukoplakia exist regarding the standardization of diagnostic criteria, risk stratification for malignant transformation, and optimization of management approaches [9]. This systematic review critically examines the literature on oral leukoplakia diagnosis and management, synthesizing clinical and histopathological aspects along with therapeutic interventions and outcomes, in order to provide an understanding about this condition that is comprehensive and evidence-based.

Eligibility criteria

The PECOS framework-which comprises Population, Exposure, Comparator, Outcome, and Study Design-was used in determining the inclusion criteria for this systematic review in accordance with the PRISMA guidelines [13]. Patients diagnosed with oral leukoplakia, confirmed both histopathologically or clinically by established diagnostic criteria, constituted the population. Any diagnostic or therapeutic intervention directed at oral leukoplakia-surgical, pharmacological, or adjunctive modalities-represented the exposure. Comparators were either untreated controls, other treatments, or no treatment at all, depending on the design of the study. The core outcomes measured were diagnostic accuracy, treatment efficiency such as clinical remission and recurrence or malignant transformation rates, and side effects. Inclusive study designs were randomized controlled trials, cohort studies, case-control studies, and observational studies with original data.

The inclusion and exclusion criteria for this systematic review were clearly defined to ensure the selection of relevant studies addressing diagnosis and treatment of oral leukoplakia. Studies involving patients with a histopathological or clinical diagnosis of oral leukoplakia are included while those studies concerning other diseases of the oral mucosa or systemic conditions unrelated to the diagnosis or treatment of oral leukoplakia are excluded. Eligible interventions were those in which any diagnostic or therapeutic intervention targeted oral leukoplakia; studies that targeted oral squamous cell carcinoma or other malignancies exclusively were excluded. Groups considered for comparison were usually either untreated controls, alternative treatments, or no intervention, based on study design. Studies that lacked a comparator group when it was essential for study design were excluded. Outcomes of interest were diagnostic accuracy, remission rate, recurrence, malignant change, and safety of treatment. Studies that did not report one or more of the aforementioned outcomes quantitatively or qualitatively were excluded.

Database Search Protocol

The systematic search involved all five databases; PubMed, Scopus, Web of Science, Embase, and Cochrane Library. The use of Boolean operators combined with relevant MeSH keywords was used in order to ensure that the search strategy covered the subject adequately. Although sensitivity and specificity were optimized, different customized search strategies for each database were used. The terms searched for included oral leukoplakia, premalignant disorders, diagnostic techniques, and therapeutic interventions by using Boolean operators such as AND, OR, and NOT. MeSH terms, synonyms, and truncation were applied where appropriate (Table 1). Results of the search were imported into a reference management tool for deduplication. Titles and abstracts of all records were independently screened for relevance by two reviewers, followed by full-text review for eligibility. Cases of discrepancies were resolved either through discussion or adjudication involving a third reviewer. All processes involved documentation for transparency and reproducibility.

Data Extraction Protocol

Data extraction was performed independently by two reviewers based on a predefined template. Extracted information consisted of study characteristics: author, year, location, design, sample size, and follow-up period; population demographics: age, sex ratio; diagnostic methods; interventions; comparators; outcomes; and statistical findings. Disagreements were resolved either by discussion or by a third-party review. Extracted items were cross-checked with the original source for accuracy and completeness. The extracted information was formatted into a structured methodology to analyze treatment efficacy, recurrence rates, and malignancy outcomes.

Bias Assessment Protocol

The ROBINS-I tool [14] was used for non-randomized studies in order to measure bias in seven domains: confounding, selection bias, classification of interventions, and outcome reporting. For randomized studies, the Cochrane RoB 2.0 tool [15] was used to evaluate randomization processes, deviations from intended interventions, missing data, and measurement of outcomes. The risk of bias level was classified as low, moderate, or high depending on predefined criteria for each study. Assessments were performed in duplicate by two independent reviewers whose disagreements were addressed by discussion

A total of 552 records were identified from database searches. Following the exclusion of 65 duplicate records, 487 unique records were screened. Of these, 34 records were excluded at the initial screening based on title and abstract relevance. Then, 453 full-text reports were sought for retrieval, but 66 reports could not be retrieved. Out of the 387 reports reviewed, 379 were excluded. The common reasons for exclusion based on predefined criteria comprised 43 case reports, 57 full-text unavailable reports, seminar articles totaling 48, reports whose objectives strayed from those set, totaling 62 studies, 82 literature reviews, and 87 thesis articles. Eight studies [16-23] later satisfied the selection criteria, thus included for qualitative and quantitative analysis.

LEGEND

Table 1: Search strings utilised across the databases

Demographic characteristics observed

The results from the demographic characters (Table 2) depict significant variations in the extent, preparation, and population characteristics of studies concerning oral leukoplakia, indicating research heterogeneity in this area. The included studies represented different geographic settings, namely the USA [16, 17], India [18], Japan [19, 22], Europe and Australia [20], Brazil [21], and China [23], thus demonstrating global interest in addressing oral leukoplakia. The study designs varied across randomized controlled trials (RCTs) [18, 19, 22], retrospective cohort studies [16, 23], a preliminary study [21], a phase 2 trial [17], and a survey-based observational study [20]. This range of study designs contributed to differences in evidence strength and generalizability. Retrospective cohort studies [16, 23] supplied retrospective data regarding outcomes such as malignant transformation and recurrence, whereas RCTs [18, 19, 22] permitted controlled comparisons of treatment modalities. The survey-based observational study [20] captured practitioner insights, emphasizing diagnostic and management variability. These varied from 18 [21] to 4886 participants [16], which reflects differences in the scale and power of a given study. Those with small sample sizes, like preliminary studies [21] or phase 2 trials [17], also had limited generalisability but cohorts with such a high number [16] provided robust statistical analyses of outcomes such as malignant transformation risk.

Table 2: Demographic characteristics of the included studies

The mean age of the participants ranged from 56 years [18] to 66 years [22], signifying that oral leukoplakia primarily affects middle-aged and older adults. Yet, not all of them reported age distribution [16, 20] which may affect comprehensive demographic analysis. Male to female ratios were also varied, showing predominantly females [21, 23] and balanced ratios [18, 19], mainly depending on gender-related variations of risk factors such as tobacco or alcohol use. Follow-up periods ranged from 9 months [21] up to 16 years [16] and therefore affected the ability to make any estimates for long-term outcome issues, such as recurrence or malignant transformation. Short follow-up periods [17, 21] captured acute therapeutic effects, but longer periods [16, 22] gave critical insights into disease progression and recurrence patterns. Studies with an undefined follow-up period [20] focused more on current practices rather than having a longitudinal outcome.

Groups Evaluated

The reviews had mixed intervention and control groups to examine the following aspects of oral leukoplakia diagnosis and management (Table 3). They included biopsied patients versus controls who had not undergone biopsy [16], treatment using new agents like nivolumab [17], curcumin versus placebo groups [18], beta-carotene and Vitamin C combination with a control of a placebo [19, 22]. Other populations studied included oral medicine practitioners from Europe and Australia [20], laser-assisted therapy groups compared to non-laser groups [21], and patients receiving ablative fractional laser-photodynamic therapy (AFL-PDT) [23]. This heterogeneity of study designs allowed for a wide-ranging exploration of diagnostic and therapeutic modalities.

Major Outcome Measures

The major outcomes differed across studies, reflecting the multi-modality nature of managing oral leukoplakia. These include cancer progression between biopsied and non-biopsied groups [16], changes in lesion score with immunotherapy [17], clinical responses in terms of reduction in the size of lesions with curcumin therapy [18], rates of remission, and malignant transformation with antioxidant interventions [19, 22]. Reducing pain was considered a primary outcome in cryosurgery that was combined with laser therapy [21], but in AFL-PDT studies, treatment efficacy, recurrence, and malignant transformation were the focus [23]. Questionnaires to practitioners established the preference for diagnosis and treatment and their differences [20].

Intervention Description

The treatments administered incorporated pharmacologic and procedural interventions. Routine biopsies were instituted to improve monitoring of cancer progression [16]. Nivolumab was also given at 480 mg every 28 days for four cycles, aiming to manage the lesion scores in progressive lesions [17]. Curcumin therapy was carried out using 3.6 g/day dosages for six months [18], while beta-carotene and Vitamin C were used at different concentrations to examine their chemopreventive effects [19, 22]. Laser-assisted treatments included cryosurgery [21] and AFL-PDT [23] with exact technical conditions for localized treatment. Treatment decisions and diagnostic conduct were guided by the statistical modeling of responses from practitioners [20].

Information about Diagnosis

The diagnosis methods were based on established criteria such as ICD-9 codes for assessing cancer progression, [16] the Van der Waal classification for proliferative verrucous leukoplakia, [17] WHO consensus criteria for curcumin studies, [18] and WHO criteria for antioxidant interventions. [19] Warnakulasuriya criteria were used in studies with cryosurgical interventions [21], and histopathological confirmation became extremely important in AFL-PDT studies. [23] Diagnostic adjuncts and their use in clinical practice were appraised during surveys with the practitioners. [20].

Figure 1: Study selection process for this review

Results and Statistics Observed

The statistical analysis was strong. In biopsied groups, the progression of cancer was substantially higher; they had an SIR of 40.8 (95% CI: 34.8–47.6) and an HR of 2.38 (95% CI: 1.73–3.28) [16]. The response rate of Nivolumab was 36% (95% CI: 20.4%–54.8%) [17], and curcumin showed a 67.5% clinical response as opposed to the placebo group 55.3% had a clinical response (p=0.03) [18]. Beta-carotene and Vitamin C demonstrated mixed outcomes, with relative risk values indicating limited statistical significance [19, 22]. Laser therapy significantly reduced pain (p<0.05) [21], and AFL-PDT showed an 87.5% positive response rate, with site-specific recurrence (OR: 1.64, p<0.001) and increased malignant risk linked to dysplasia severity (OR: 2.93, p=0.02) [23]. Practitioner surveys revealed that 83% routinely performed biopsies, with significant geographic variations (p<0.001) [20].

Figure 2: Assessment of bias using the RoB 2.0 tool.

Bias assessment observations

Studies conducted using the RoB 2.0 tool (Figure 2) differ in the levels of concern across the domains. One study resulted in a low risk throughout all domains except "Outcome Reporting" (D5) where some concerns were noted [17]. The other study showed a low risk in the randomization process (D1) but it stated its concerns on several domains, including deviation from intended interventions (D2) and outcome measurement (D3-D5) [18]. Several studies had concerns in most domains, especially on their handling of confounding factors and deviations from protocol [19, 21, 22]. Yet one study somehow scored an overall low risk of bias despite having minor concerns in certain aspects of the domains [22]. This variability brings out the discrepancies in study designs and conducts that may have affected the outcome.

The ROBINS-I tool (Figure 3) used for assessing showed generally low risk of bias for all studies. One study had the majority maintained a low risk but "Confounding" (D3) at moderate risk [16]. Another was scored low bias in all domains except the one for "Bias in the Selection of Reported Results" (D7), which was at moderate risk due to incomplete reporting of outcome data [20]. Similarly, a third study demonstrated moderate bias in confounding (D2) and selective reporting (D5), but overall bias was rated as low [23].

Figure 3: Assessment of bias using the ROBINS-I tool

In total, these studies together pointed out diverse approaches and outcomes associated with oral leukoplakia diagnosis and management, areas of similarity and divergence prevailing in them. A few studies on interventions like curcumin [18] as well as AFL-PDT [23] showed impressive clinical results but via different mechanisms and endpoints. Curcumin provided improvement in lesion size outcomes but failed to offer sustained benefits [18]. AFL-PDT notably minimized lesion recurrence and risks of malignant transformation with proper site-specific considerations [23]. Both demonstrated the possibility of targeted therapies as a tool for significant burden reduction.

Beta-carotene and Vitamin C interventions presented scant or null statistiscal gains in the prevention of malignant transformation [19, 22], making both studies comparable in their conclusions about the little value of chemopreventive agents. Their results were divergent from the activity seen in the nivolumab-treated groups, where promising improvements in lesion scores were recorded, and further validation via larger trials was suggested [17].

Overlapping themes were observed within studies focused on diagnostic practices. Routine biopsies were considered crucial in determining the risk, especially for dysplastic lesions, with resultant important implications in the cancer course [16]. However, survey findings pointed to a lack of agreement among practitioners on the diagnostic and management approaches to oral leukoplakia, and their consistency was geographical and demanded harmonized guidelines [20].

Laser-based treatments, including LLLT [21], gave a good symptomatic response, in part mirroring the results achieved by AFL-PDT [23] but with different endpoints (pain relief vs recurrence / malignancy). The symptomatic focus of LLLT diverged from the more holistic disease-modifying potential seen with AFL-PDT.

All in all, studies of curcumin [18] and AFL-PDT [23] exhibited convergence on demonstrated effectiveness, whereas interventions on chemoprevention [19, 22] were highly divergent because they did not yield substantial outcomes. Diagnosis studies [16, 20] pointed to convergence in the stress of biopsy but did diverge on consistency of practice. The emerging trends for both diagnosis and therapy underline the need for further research to harmonize diagnostic and therapeutic practices while advancing the creation of effective interventions.

Leukoplakia may occur in any oral cavity location, although most frequent sites are the floor of the mouth and the ventral surface of the tongue. It is often located under the tongue and is termed sublingual keratosis and its incidence is of more worrisome risk of malignancy than leukoplakia at other sites, often referred as lower risk [24]. Most often, it is asymptomatic, but some patients do notice ulcers that fail to heal with the progressing lesion [16]. More advanced stages present with bleeding, ability to wear the dentures, mobility of the teeth, dysphagia, odynophagia, and neck masses, amongst others by speech difficulties [25].

Clinical examination is mostly dependent on visual and then tactile inspection [26]. A preliminary diagnosis of leukoplakia is established when a persistent white patch is observed after ruling out potential traumatic causes. Such lesions are characterized by their inability to be removed through scraping and a lack of color change when the tissue is stretched. It is also necessary to exclude other conditions presenting as white lesions during the clinical examination [4]. The earliest detection of these lesions is still a challenge, since many only seek medical attention when their condition has reached advanced stages, that is Stage III or IV [27]. Oral leukoplakia is always diagnosed by exclusion, therefore other causes of white oral lesions are eliminated before confirmation. If aggravating factors are suspected, these should be dealt with and re-evaluated after 2 to 4 weeks. Persistent lesions after this period need to be biopsied in order to confirm diagnosis and assess malignant potential. Biopsy samples should be obtained from the regions showing redness, erosion, ulceration, or induration, but for large or multifocal lesions, multiple biopsies may be necessary [28]. Biopsy is advised for all cases of leukoplakia irrespective of clinical features, size and extent of lesion, and location in the oral cavity [29].

The risk of oral premalignant lesions to evolve into cancer varies from less than 1% to as high as 18%. Nonetheless, certain subtypes of leukoplakia have a higher tendency for malignant transformation. Some of the factors that determine malignancy include epithelial neoplasia which is believed to be more influential compared with clinical features only [30-32]. The predictors include lesion size, clinical subtype, location, and presence of epithelial dysplasia, although their application to individual cases often lacks reliability [16]. In the case of proliferative verrucous leukoplakia, the long-term prognosis is still poorly understood [33]. Some studies have stressed the significance of dysplastic changes that are involved with carcinoma in situ and evaluated factors such as p53, keratins, epidermal growth factor receptor, and chromosomal instability that could explain parts of the carcinogenesis process and support the theory of field cancerization [34]. These results are in accord with the new theories of tumorigenesis that describe not only alterations of molecular nature within the area but also the formation of multiple lesions. Further, larger lesions have been known to have a higher incidence of malignant transformation than smaller localized ones [35-38].

Limitations

Several limitations have been encountered in this study to impact the comprehensiveness as well as the generalizability of findings. Variability in the sample sizes and the study designs introduced heterogeneity, complicated direct comparisons of outcomes, while dependence on different diagnostic criteria and outcome measures across studies did limit uniform conclusions. Other limitations were that some of the included studies had small sample sizes or very short follow-up times, which limited analysis for recurrence and malignant change. Differences in reporting included lack of demographic information or incomplete statistical information, which also narrowed possible interpretation. Geographic regional variability in diagnostic and therapeutic approaches underscored the lack of standard guidelines applied uniformly, which may likely have affected practitioners' responses and clinical practices.

Clinical recommendations

Based on the findings, routine biopsies are recommended to become a critical component of risk assessment, but they should always be limited to lesions showing dysplasia. The use of targeted therapies like AFL-PDT will be beneficial in decreasing recurrence and malignant change, but chemopreventive agents could be partially deprioritized due to its slight and minimal benefits. Long-term studies with larger sample sizes are required to validate the effects of emerging therapies and measure outcomes such as malignant transformation. The development of standardized diagnostic and management protocols will create uniformity of care across geographic regions and improve clinical outcomes. Education and training programs on evidence-based approaches for practitioners must fill in the knowledge gaps and reduce variability in clinical practice.

This systematic review showed different approaches in the diagnosis and treatment of oral leukoplakia, thus reflecting routine biopsies and targeted therapies as an important component in risk stratification and disease management. However, for interventions like curcumin or AFL-PDT, promising results can be seen in terms of lesion size reduction and recurrence. But beta-carotene and Vitamin C chemopreventive agents showed a limited benefit of reducing the formation of leukoplakia, leaving place for alternative strategies. This explained the need for standardizing guidelines and further research for better patient outcomes as the lack of consensus among practitioners and significant variability in diagnostic and therapeutic practices could not be overlooked.

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