Prevalence of oral submucous fibrosis across diverse populations: a systematic review and meta-analysis

Introduction

Oral submucous fibrosis (OSF) is a chronic disease that progressively restricts mouth opening due to fibrous bands in the oral mucosa (Vohra et al., 2015). This condition is commonly linked to betel quid chewing, especially prevalent in South and Southeast Asia. This leads to symptoms such as burning pain and lockjaw, which significantly impair various oral functions, thereby greatly affecting the patient’s quality of life (Bhatt et al., 2019). OSF is identified by the World Health Organization (WHO) as a high-risk precancerous condition for oral squamous cell carcinoma (OSCC), with reported malignant conversion rates of up to 6% in some studies (Kujan, Mello & Warnakulasuriya, 2021; Warnakulasuriya et al., 2021). Hence, it poses a considerable threat to long-term health outcomes. Currently, due to its irreversibility, OSF cannot be cured by any effective treatment method, despite ongoing clinical trials and various therapeutic approaches (Rao et al., 2020). Prevention remains the sole viable option for clinicians to address OSF.

According to WHO data, there are approximately 5 million cases of OSF worldwide, with distinct geographical patterns (Yuwanati et al., 2023). Among countries with a high prevalence of OSF, Southeast Asian nations account for the largest proportion, constituting 10.54% of cases (Mello et al., 2018). Predominantly reported in India, OSF cases have also been documented in other regions such as Indonesia, Bangladesh, southern China, Thailand, Sri Lanka, and Nepal (Yuwanati et al., 2023). Its prevalence extends beyond Asia, with reported cases in Europe and North America (Mostafa et al., 2021). However, the majority of studies reporting the prevalence of OSF are either hospital-based or rely on conveniently selected research cohorts, potentially failing to reflect the true prevalence of OSF. Furthermore, the etiological factors associated with OSF are multifaceted, including autoimmunity (Gupta et al., 2022), nutritional deficiencies such as vitamins B and C, and iron (Wang et al., 2015), the consumption of spicy foods (Wang & Tang, 2022), human papilloma virus (HPV) infection (Sudhakaran, Hallikeri & Babu, 2019), genetic mutations (He et al., 2020), as well as the consumption of betel nuts, smoking, and alcohol, which are notably correlated with the progression of OSF (Ray, Chatterjee & Chaudhuri, 2019). Regions with high rates of betel nut production and consumption often exhibit elevated incidences of OSF (Rao et al., 2020). However, not all individuals who indulge in betel nut chewing develop OSF (Sarode et al., 2013). Additionally, research indicates that 93% of OSF patients have a history of tobacco product use, with a significant portion also exhibiting alcohol consumption habits (Karthikeyan, Ramasubramanian & Ramanathan, 2020). Therefore, the etiology of OSF is currently considered multifactorial and unclear, despite significant research efforts aimed at elucidating its pathogenesis.

To comprehensively delineate the epidemiological profile of OSF, several meta-analyses investigating its prevalence have been conducted. Yuwanati et al. reported a prevalence rate of 5% among betel nut chewers without performing subgroup analyses based on factors such as age, gender, and country (Yuwanati et al., 2023). Meanwhile, Mello et al.’s (2018) meta-analysis indicated a prevalence rate of 4.96% for OSF. However, their exclusion of studies examining population exposure to risk factors may limit the comprehensive representation of OSF prevalence worldwide. This systematic review and meta-analysis seeks to comprehensively determine the global prevalence of OSF across various demographic groups and geographical locations, thereby filling the existing knowledge gaps in the epidemiology of this condition

Material and Methods

This systematic review and meta-analysis was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and has been prospectively registered on the PROSPERO website (CRD42024532975) (Page et al., 2021).

Results

Studies selection

A total of 63 studies met the inclusion criteria, with data extracted from diverse populations across various continents, representing a comprehensive analysis of OSF prevalence globally (Agrawal et al., 2021; Al-Attas et al., 2014; Ali et al., 2017; Alvarez Gomez et al., 2008; Amarasinghe et al., 2010; Ariyawardana et al., 2007; Arjun et al., 2014; Bhatnagar et al., 2013; Byakodi et al., 2011; Chandra & Govindraju, 2012; Chatterjee, Gupta & Bose, 2015; Chiang et al., 2014; Chung et al., 2005; Dagli et al., 2008; Gupta et al., 1989; Gupta et al., 1998; Gupta et al., 2012; Hallikeri et al., 2018; Ikeda et al., 1995; Jacob et al., 2022; Jose et al., 2023; Kaur, Chauhan & Shivakumar, 2023; Krishna Priya, Srinivas & Devaki, 2018; Kumar et al., 2015; Kumar et al., 2019; Kumar Srivastava, 2014; Lee et al., 2011; Liu et al., 2022; Mathew et al., 2008; Mehrotra et al., 2017; Mehrotra et al., 2008; Mehrotra et al., 2010; Nair et al., 2014; Nigam et al., 2014; Oakley, Demaine & Warnakulasuriya, 2005; Oswal et al., 2023; Patil, Bathi & Chaudhari, 2013; Patil, Doni & Maheshwari, 2015; Pindborg et al., 1968; Pindborg et al., 1984; Rajendran et al., 1992; Rani et al., 2023; Reddy et al., 2015; Reddy et al., 2012; Rooban et al., 2009; Sankaranarayanan et al., 2000; Saraswathi et al., 2006; Sari et al., 2024; Seedat & Van Wyk, 1988; Shrestha et al., 2023; Singh et al., 2023; Sujatha, Hebbar & Pai, 2012; Sumithrarachchi et al., 2024; Tang et al., 1997; Thavarajah et al., 2006; Verma & Sharma, 2019; Villa & Gohel, 2014; Yang et al., 2005; Yang et al., 2010; Yang et al., 2001; Yunus et al., 2019; Zain et al., 1997; Zhang et al., 2012a). The methodology and progression of our research are visually depicted in Fig. 1.

Prevalence of OSF

Our research findings reveal a comprehensive prevalence of OSF across all populations at 3.0% (95% CI = 2.8−3.2%). Furthermore, based on the sampling or selection methods employed in the included studies to assess oral mucosal status, we categorized the surveyed populations into non-risk populations, risk populations, and consecutive dental patients. Our results indicate that the prevalence of OSF is lowest in the non-risk population, standing at 2.4% (95% CI = 2.1−2.6%), higher in the risk population at 4.5% (95% CI = 3.5−5.6%), and highest in consecutive dental patients, reaching 5.6% (95% CI = 3.8−7.5%). Figure 2 illustrates the comprehensive prevalence of OSF across all populations and the respective prevalence of OSF within each population.

Additionally, subgroup analysis of OSF prevalence based on gender, age, and region is presented in Fig. 3. Notably, we observed a higher prevalence of OSF in males at 3.3% (95% CI = 2.9−3.7%) compared to females at 1.0% (95% CI = 0.8−1.2%). Regionally, India exhibits the highest prevalence of OSF at 4.0% (95% CI = 3.7−4.3%), while the United States demonstrates the lowest prevalence at 0.3% (95% CI = 0.0−1.0%). Regarding age, individuals over 50 years old exhibit the highest OSF prevalence at 4.2% (95% CI = 3.0−5.4%), whereas the prevalence is relatively lower around 3.2% in individuals under 40 years old and those aged 40–50 years.

The subgroup analysis results for different types and degrees of risk factors contributing to OSF are depicted in Fig. 4. The pooled prevalence of OSF was found to be higher in populations with a predominant habit of betel quid chewing, as compared to other regions where this habit is less common, indicating a strong correlation between the two factors. Meta-regression analysis further suggests that tobacco use predominantly explains the heterogeneity source (see Supplementary Materials 3–5).

Discussion

The present meta-analysis revealed that the prevalence of OSF was 3.0% in the overall population, 2.4% in the non-risk population, and reached 5.6% in consecutive dental patients. Despite the comprehensive nature of the data considering factors such as gender, age, habits, region, and exposure to risk factors, it should be noted that the included studies were all cross-sectional, which introduces heterogeneity and limitations (such as high risk of bias) to the original data. Therefore, these estimates should be interpreted with caution. Nevertheless, given the irreversible nature of OSF as a precancerous lesion and its significant economic impact on individuals and healthcare systems, these figures remain concerning and warrant further attention.

This review examined the prevalence of OSF across different genders, countries, and age groups. The results indicate a threefold higher prevalence of OSF in males compared to females. Disparities in the male-to-female ratio of OSF patients were observed across various regions, seemingly correlated with chewing habits prevalent in those areas (Hazarey et al., 2007; Shih et al., 2019; Yang et al., 2018). India reported the highest OSF prevalence, while the United States reported the lowest. Consistent with previous studies, the Indian subcontinent exhibits a high prevalence of OSF (More et al., 2018), with India having the highest incidence of OSF among the studied nations (Ray, Chatterjee & Chaudhuri, 2019). The elevated prevalence in India is attributed to the increased popularity of commercially prepared Areca betel nut products (Cai & Huang, 2022). Developed countries have consistently shown lower OSF incidence rates, possibly due to the presence of substantial migrant populations (Shen et al., 2020). Furthermore, the higher prevalence observed in socioeconomically disadvantaged areas is a cause for concern, as these regions often indicate relatively poorer access to healthcare services and lower levels of treatment adherence, factors that can have a significant impact on disease progression. Additionally, while the prevalence of OSF tends to be higher in individuals over 50 compared to younger demographics, the difference is not significant.

The pathogenesis of OSF is multifaceted, involving inflammation, hypoxia, and reactive oxygen species generation (Lin et al., 2019; Mohammed et al., 2015; Shen et al., 2020). While OSF etiology is multifactorial, extensive research has highlighted habits such as betel nut chewing, tobacco use, and alcohol consumption as significant risk factors for OSF (Aishwarya et al., 2017; Liu et al., 2015; Zhang et al., 2012b). A previous meta-analysis reported a low prevalence (5%) of OSF among areca nut chewers, contradicting the strong association between areca nut chewing and OSF (Yuwanati et al., 2023). Our meta-analysis conducted subgroup analyses based on the percentage of Areca betel nut use, tobacco use, and alcohol use within the surveyed populations, revealing a pronounced increase in OSF prevalence when these risk factors were prevalent. This trend is most notable in tobacco use. Consistent with previous findings, concurrent use of betel nut and tobacco significantly escalates OSF incidence, suggesting a synergistic effect of tobacco consumption and betel nut chewing on OSF occurrence (Cirillo et al., 2022). Although current epidemiological research underscores betel nut chewing as the foremost risk factor for OSF, this study implies that betel nut may not be the sole causative agent of OSF. Thus, previously underappreciated risk factors for OSF, such as tobacco use, warrant greater attention, prompting the formulation of pertinent public health policies and health promotion initiatives.

This study introduces the systematic secondary review of literature on prevalence of OSF, aiming to estimate the overall incidence by integrating multifactorial, cross-population data. It holds significant value for uncovering the societal health burden of OSF, providing a scientific foundation for the development of public health care plans, and assessing the effectiveness of prevention and treatment strategies. While most existing studies concentrate on Southeast Asia, limiting a comprehensive view of the global prevalence of OSF. This research calls for broader geographical research to fill gaps in our knowledge, as the dynamic progression of OSF and undefined etiology suggest that low-prevalence regions could reveal additional contributing factors beyond diet. Besides, quality assessment revealed methodological deficiencies and inconsistent diagnostic criteria, causing heterogeneity in secondary research. Future research should prioritize methodological clarity and diagnostic standardization to enhance the reliability of findings and support robust public health policy-making in addressing OSF challenges.

While the overall quality of the studies included remains relatively low, this meta-analysis significantly mitigated the adverse effects of heterogeneity on the results by stratifying the data. By categorizing the sampled populations into three groups based on the sampling method, this meta-analysis greatly reduced the impact of sampling methodology-induced heterogeneity, thus making the pooled prevalence of OSF more closely approximate the true value. OSF Additionally, subgroup analyses based on gender, geographical region, and age demonstrated epidemiological characteristics of OSF. Furthermore, subgroup analyses based on variations in the types and extents of risk factor exposures within the surveyed populations provided additional perspectives for preventing and treating OSF. However, our study still possesses certain limitations. Firstly, not all studies reported their diagnostic criteria for OSF, potentially introducing measurement bias due to variations in the level of experience and subjective perspectives among examining physicians. Secondly, we did not further stratify the risk population into subgroups based on different levels of risk factors exposure, which may have limited the depth of our results. Moreover, despite conducting subgroup analyses, substantial heterogeneity still existed, indicating that we may not have fully elucidated the sources of heterogeneity. Oral manifestations of OSF may not have been evident during the data collection period due to the variability in disease severity at its onset and the significant heterogeneity in treatment response. Consequently, conducting longitudinal investigations becomes crucial in order to provide a deeper understanding of the prevalence of oral symptoms associated with OSF at various stages of the disease.

Conclusions

Our research findings reveal a comprehensive prevalence of OSF across all populations at 3.0% (95% CI = 2.8−3.2%). And, existing evidence indicates a relatively low prevalence of OSF associated with tobacco, alcohol, and Areca (betel) nut use. However, further large-scale studies are recommended to validate these findings. Understanding the prevalence and distribution patterns of OSF may assist in healthcare intervention planning and alleviate the oral cancer burden associated with OSF.

Supplemental Information