Global expert consensus on oral submucous fibrosis: Standardizing care, surveillance, and prevention strategies

Abstract

Background:

Oral submucous fibrosis (OSF) is a chronic, progressive, and irreversible fibrotic disorder of the oral mucosa that is strongly associated with areca nut consumption. It is classified as an oral potentially malignant disorder (OPMD) with one of the highest malignant transformation rates (4%–7%). Despite extensive research across Asia and globally, significant heterogeneity persists in diagnostic criteria, grading systems, and management strategies. This hinders effective clinical practice, surveillance, and public health policymaking. By integrating translational evidence on areca nut–associated fibrosis, oral potentially malignant disorders, and oral cancer into a consensus-driven framework, this manuscript advances biologically informed, equitable, and collaborative strategies for oral cancer prevention and early risk reclassification in resource-limited settings.

Methods:

This guideline was developed through a structured consensus process modelled on the ACCORD reporting framework for consensus-based biomedical research. A multi-institutional steering committee was convened, and included senior oral pathologists and clinicians: Vinay Hazarey (VH), WM Tilakaratne (WMT), Kannan Ranganathan (KR), Raghu Radhakrishnan (RR), Jayanta Chattopadhyay (JC), Punnya V Angadi (PA), Karishma Desai (KD), and Pratibha Ramani (PR) (as a moderator from Saveetha Dental College, Chennai). The panel head was Dinesh Daftary (DD). Evidence was synthesised from peer-reviewed publications indexed in PubMed, Scopus, and Web of Science. Consensus was defined as ≥80% agreement following structured rounds of discussion. The recommendations were graded as Strong or Conditional according to the quality of evidence, feasibility, and global applicability.

Results:

The panel achieved a consensus on key areas: (1) OSMF is caused primarily by areca nut, a Group I carcinogen with no safe level of use; (2) clinical diagnosis should combine functional limitations with mucosal changes, supported by histopathology that incorporates fibrosis severity and epithelial dysplasia; (3) management should prioritize habit cessation, supplemented by pharmacological and surgical interventions as appropriate; (4) malignant transformation warrants long-term surveillance and potential revision of staging for OSMF-related oral cancer; and (5) strong public health measures are urgently needed, including regulation of areca nut sales and the establishment of centres of Excellence for OPMDs.

Conclusions:

These WHO-style guidelines provide an evidence-based, globally relevant framework for the diagnosis, management, and prevention of OSMF. The emphasis should be on early detection, habit cessation, translational research, and policy reforms. The adoption of these recommendations will strengthen clinical practice and reduce the burden of OSMF, and associated oral cancer worldwide.

INTRODUCTION

Oral submucous fibrosis (OSMF) is recognised as one of the most significant oral potentially malignant disorders (OPMDs), affecting millions of individuals globally, with the highest prevalence in South Asia, Southeast Asia, and Pacific Island nations. The disease is chronic, irreversible, and progressive, leading to mucosal stiffness, trismus, and functional disability.[1] Its malignant transformation rate, estimated to be between 4% and 7%, is among the highest reported rates for OPMDs, underscoring its oncological significance.[2]

Although historically concentrated in India, Bangladesh, Sri Lanka, and Taiwan, globalisation of areca nut consumption through migration and trade has contributed to rising incidence in Europe, the Middle East, and North America.[3] This reflects the cultural export of areca nut products, including gutka, pan masala, and flavoured supari. With more than 600 million people worldwide estimated to use areca nut in some form, OSMF represents both a regional epidemic and a growing global concern.[4]

The disease was first described in the mid-20^th century, but earlier accounts in Ayurvedic texts described restricted mouth opening and intolerance to spicy foods, which are consistent with OSMF-like features. VH emphasised the continuity of these descriptions, linking cultural chewing practices to the current epidemic.[5] The recognition of areca nut as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC) has reinforced the global imperative for preventive action.[6]

Areca nut is the principal etiological factor. Both raw and processed forms, including gutka and pan masala, have strong fibro genic potential. Additives such as tobacco exacerbate carcinogenicity, and the carcinogenic potential of slaked lime needs more research. PA highlighted that the fibro genic effects of the areca nut are promoted by alkaloids such as arecoline, which lead to persistent fibroblast activation and collagen deposition through TGF-β-driven pathways, a crucial cytokine in the development of OSMF.[7] Genetic susceptibility further modulates risk: cytokine polymorphisms, detoxification enzyme variants, and HLA associations have been reported, as highlighted by RR. PA emphasised that despite extensive research on various biomarkers, their clinical effectiveness is still uncertain.[8]

JC highlighted regional variations in disease drivers, noting that in eastern India, children and adolescents are disproportionately affected due to the widespread availability of low-cost sachets. RR and PA emphasised the role of host biology, including fibroblast heterogeneity and epithelial–mesenchymal transition (EMT), in disease persistence. PA also noted the specific site characteristics of OSMF, pointing out that the gingiva and periodontal ligament are less affected due to the dynamic ECM remodelling and the adaptive nature of gingival fibroblasts.[9]

OSMF presents unique clinical challenges. Early stages are characterized by burning sensation and mucosal blanching, progressing to palpable fibrosis and reduced mouth opening. Advanced stages can lead to severe trismus, impair speech, mastication, and nutrition. In addition to physical morbidity, OSMF contributes to psychological distress and a reduced quality-of-life.[10]

From a public health perspective, the disease exemplifies the interface of lifestyle habits, social determinants, and cancer epidemiology. The absence of standardized diagnostic and therapeutic protocols has resulted in wide variability in care delivery. Patients often present late, and interventions are inconsistently applied. This perpetuates the cycle of morbidity, disability, and malignant progression.[11]

Although numerous narrative reviews and small-scale guidelines exist, there are no universally accepted, WHO-endorsed guidelines for the management of OSMF. Inconsistent terminology, staging, and management recommendations have limited effective policy adoption. Furthermore, there is an urgent need to address the public health dimensions of areca nut use—paralleling global frameworks for tobacco control.[12]

WMT emphasized the oncological urgency of standardized guidelines, noting that oral squamous cell carcinoma (OSCC) arising from OSMF behaves differently from conventional OSCC, often exhibiting reduced nodal spread but aggressive exophytic growth. This necessitates a tailored staging and treatment framework.[13] KR concluded that without international consensus, OSMF risks remain an under-recognized but high-impact disease. KR advocated for guidelines that integrate clinical, pathological, molecular, and policy dimensions, anchored in both evidence and expert consensus.[14]

The WHO Global Oral Health Action Plan emphasizes the prevention and control of oral cancer and OPMDs as part of the non-communicable disease agenda. The incorporation of OSMF within this framework aligns with broader efforts to regulate carcinogenic exposure, reduce health inequities, and strengthen surveillance. By framing OSMF as a public health priority, these guidelines seek to catalyse both national-level interventions (regulation of areca nut, awareness programs), and international collaborations (research networks, funding support).

METHODS

Framework for consensus development

The methodology for these guidelines was designed according to the principles of the ACCORD framework for accurate consensus reporting and the WHO Handbook for Guideline Development. The process prioritised transparency, inclusivity, and reproducibility. The key methodological steps included the formation of a steering committee to oversee the scope, methodology, and consensus process; selection of expert panellists through predefined eligibility criteria; systematic synthesis of peer-reviewed literature; structured consensus rounds incorporating moderated discussions and formal voting; and grading of recommendations as strong or conditional depending on evidence quality, feasibility, and public health relevance.

Establishment of the steering committee

DD (Panel Head), an eminent academician and a stalwart in oral pathology and maxillofacial diagnostics, has long been respected for his contributions to evidence-based clinical research, policy shaping, and postgraduate education across India. DD’s participation in the consensus deliberations brought not only gravitas, but also forward-thinking insights that enriched the discussion on OSMF. The Steering Committee is composed of nationally and internationally respected oral pathologists.

VH, Adjunct faculty, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India is a pioneering figure in OPMD research and tobacco cessation advocacy, having led some of India’s earliest community-based screening, and habit intervention programmes. His current work also presents metronomic chemotherapy as a possible adjunct for the management of the dual pathology—OSMF with proliferative verrucous leukoplakia.

WMT, Professor at the Faculty of Dentistry, University of Malaya, Malaysia, and former dean of the University of Peradeniya, Sri Lanka, brought global authority to the panel through his seminal contributions to WHO OPMD classifications and cohort-based studies across South Asia and Southeast Asia.

KR, Professor and Head of Oral Pathology at Ragas Dental College, Chennai, provided strategic leadership in evaluating patient-reported outcomes, surveillance models, and multicentric datasets, emphasising the translational relevance of population-based research.

RR, Head of Global Partnerships, Industry and Community Engagement at Oman Dental College, Muscat, and Professor at Manipal College of Dental Sciences, Manipal, bolstered by prestigious fellowships such as Marie Curie and Welcome Trust, contributed his expertise in the molecular pathogenesis of OSMF and OPMD.

JC, HOD, Principal, Kusumdevi Sunderlal Dugar Jain Dental College, Kolkata is a widely respected academic known for his work in community oral health, oral potentially malignant disorders, and the integration of histopathology with public health initiatives. His focus on the eastern Indian population has advanced understanding of region-specific aetiopathogenesis in OSMF and oral leukoplakia.

PA, Professor of Oral Pathology at KLE VK Institute of Dental Sciences, KAHER Belagavi, added critical histopathological insights into epithelial–stromal interactions, myofibroblast biology, and grading variability in OSMF. Her extensive work has elucidated the pivotal role of myofibroblasts and epithelial–mesenchymal transition in the pathogenesis and progression of OSMF.

KD, a consultant oral pathologist affiliated as a postdoctoral fellow with the Tokyo Dental College, Japan, contributed cutting-edge perspectives on OPMDs, including OSMF, artificial intelligence and oral cancer, senescence, mitochondrial bioenergetics, and stem cells.

The Steering Committee was convened under the moderation of PR, Professor and Head, Department of Oral Pathology at Saveetha Dental College and Hospital. Members were carefully selected to represent both geographic and disciplinary diversity, ensuring balanced expertise across oral pathology, oncology, molecular biology, public health, and translational science [Table 1].

Table 1.

Panel member

Name of Panel Member	Affiliation	Area of expertise	Key topic for consensus
Dr. Daftary (Panel Head)	Eminent Oral Pathologist	Consensus methodology, epidemiology	Oversight, national surveillance, malignant transformation
Dr. Vinay K. Hazarey	Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune	Public health, habit cessation	Epidemiology, community prevention
Dr. W. M. Tilakratne	University of Malaya	Histopathology, malignant transformation	Dysplasia grading, TNM modifications
Dr. Kannan Ranganathan	Ragas Dental College	Clinical management, addiction biology	Habit-cessation strategies, translational research
Dr. Raghu Radhakrishnan	Manipal College of Dental Sciences	Molecular oncology	HOX genes, genetic susceptibility
Dr. Jayanta Chattopadhyay	Kusumdevi Sunderlal Dugar Jain Dental College, Kolkata.	Community oral health	Regional epidemiology, sociocultural determinants
Dr. Punnya Angadi Rao	KLE VK Institute of Dental Sciences, Belagavi	Histopathology, EMT biology	Fibroblast heterogeneity, EMT
Dr. Karishma Desai	Tokyo Dental College, Japan	OPMDs, senescence	Senolytics, translational therapeutics
Dr. Pratibha Ramani (Moderator)	Saveetha Dental College	Consensus facilitation, genetic markers	Ethical issues, gene-environment interactions

Evidence review

A systematic evidence review was undertaken to ensure that all recommendations were grounded in peer-reviewed scientific literature. The databases searched included PubMed, Scopus, Web of Science, and the Cochrane Library, covering the period from 2010 to 2025. The search terms included a wide range of relevant keywords, including oral submucous fibrosis, OSMF diagnosis, areca nut, fibrosis, oral potentially malignant disorder, oral squamous cell carcinoma OSMF, epithelial dysplasia OSMF, habit cessation, platelet-rich fibrin (PRF) OSMF, and fibrosis biomarkers. Studies were included if they included human research such as case–control, cohort, or randomized controlled trials, as well as systematic reviews and meta-analyses directly addressing OSMF. The exclusion criteria were case reports or small case series without broader generalizability, studies focusing solely on head and neck cancers without OSMF-specific data, and non-English publications unless an English abstract was available.

The review identified approximately 400 relevant studies [Figure 1]. The evidence has been grouped thematically under epidemiology, molecular pathogenesis, diagnostic systems, management strategies, malignant transformation, and public health interventions. Panellists were assigned domains according to their expertise: for instance, VH reviewed historical and public health data, RR synthesized findings on genetic susceptibility, and WMT assessed evidence on histopathological and malignant transformation. Each expert presented a summary of findings in structured sessions, providing the foundation for consensus formulation.

Figure 1.

PRISMA Flow chart

To further emphasize the malignant potential, DD drew attention to follow-up data from the National Areca Nut Intervention Alliance (NAIA) cohort, where a total of 3,343 malignant transformations were documented, with 393 cases directly linked to OSMF. These figures, DD noted, are not merely statistical observations, but also markers of a deepening public health crisis. Also, DD strongly advocated for the development of national surveillance mechanisms and risk-based screening protocols, particularly in endemic regions.

DD also offered a compelling epidemiological insight related to regional differences in areca nut practices, highlighting that in Maharashtra, users more commonly swallow the areca quid rather than spit it out, which may result in prolonged oesophageal exposure to alkaloids. This raised a critical yet underexplored clinical question: Could chronic ingestion contribute to mucosal transformation beyond the oral cavity, particularly in the oesophagus? Although preliminary data suggest no clear oesophageal involvement in OSMF patients, DD underscored the need for longitudinal, systemic investigations—especially in populations exhibiting non-traditional consumption habits.

Consensus rounds and voting

The consensus process followed three structured stages. In the first stage, each expert delivered thematic presentations supported by evidence, followed by moderated group discussions led by the Steering Committee chair. In the second stage, draft consensus statements were formulated in real time, with iterative refinements to ensure clarity and feasibility. In the third stage, statements were formally voted upon. Consensus was defined as ≥80% agreement among panellists, in line with international Delphi standards. Voting was conducted anonymously via electronic polling to minimise peer influence, with options ranging from Strongly Agree to Strongly Disagree and Abstain. Statements failing to reach the threshold were revised, re-discussed, and re-voted in subsequent rounds. Divergent opinions were explicitly documented to maintain transparency. Each statement was scored on a five-point Likert scale (Strongly Agree to Strongly Disagree). Percentage agreement was calculated as the proportion selecting ‘Agree’ or ‘Strongly Agree’. Statements with ≥80% agreement were accepted; those below threshold underwent revision and re-voting. Divergent opinions and rationale for minority disagreement were documented to ensure methodological transparency.

Grading of recommendations

Recommendations emerging from this process were graded according to WHO standards. A strong recommendation was issued where evidence was of high quality and/or where there was unanimous panel agreement on clinical and public health importance. Conditional recommendations were used where evidence was of lower quality, where feasibility concerns were present, or where further validation was required before universal adoption. This grading system ensured that the recommendations reflected not only scientific rigour, but also contextual applicability across diverse global settings.[15]

Documentation of expert contributions

The contributions of individual panellists were formally documented to ensure transparency and recognition of intellectual input. For example, VH contributed historical context and insights into community-based prevention and metronomic chemotherapy; WMT presented evidence on malignant transformation and dysplasia grading; and KD provided translational insights from senescence biology, mitochondrial bioenergetics, role of TGF-β and omics. Such explicit attribution strengthens the credibility of the recommendations and aligns with best practices for consensus reporting.

Ethical considerations

Ethical considerations were also integrated. As this process did not involve patient-level data, no ethical approval was needed. The panel adhered to WHO principles of equity and transparency. All participants declared potential conflicts of interest, none of which were deemed significant enough to bias the outcomes. Participation was voluntary, and all consensus statements were endorsed collectively.

Reporting standards

Finally, this manuscript complies with the ACCORD reporting checklist for consensus-based publications, adapted for the WHO guideline format. Reporting elements explicitly addressed include the definition of consensus threshold, criteria for panellist selection, documentation of voting rounds and outcomes, and transparent reporting of disagreements and limitations. By adhering to these standards, this guideline aims to set a benchmark for rigorous consensus reporting in the field of oral pathology and public health [Figure 2].

Figure 2.

Consensus development steps

RESULTS

Epidemiology and public health perspectives

Epidemiological evidence confirms that OSMF is no longer a regional disorder confined to South Asia, but rather a global oral health concern [Figure 3]. Prevalence rates in India vary between 1.5% and 4% depending on the region, with the highest burden in Andhra Pradesh, Gujarat, and West Bengal [Figure 4]. JC emphasized the alarming trend of early-age initiation in eastern India, where sachet-based gutka and pan masala are marketed aggressively at very low cost. This, JC argued, has created an ‘intergenerational epidemic’, with adolescents and even schoolchildren presenting with early OSMF symptoms.

Figure 3.

Distribution of OSMF. OSMF = Oral submucous fibrosis

Figure 4.

Prevalence of OSMF. OSMF = Oral submucous fibrosis

Migration has extended this burden beyond Asia. Cases are increasingly reported in Europe, the Middle East, and North America, often in South Asian diaspora communities [Table 2]. VH reminded the panel that even ‘plain supari’, often perceived as harmless, has equal fibro genic potential. VH underscored that the International Agency for Research on Cancer (IARC) has unequivocally classified areca nut as a Group 1 carcinogen independent of tobacco.

Table 2.

Global and regional prevalence of oral submucous fibrosis

Region/country	Reported prevalence (%)	Age group most affected	Key drivers
India (Andhra Pradesh, Gujarat, West Bengal)	1.5–4	Adolescents, young adults	Gutka, pan masala, supari
Bangladesh	2–3	Young adults	Raw areca nut + tobacco
Sri Lanka	1–2	Adults	Betel quid with lime
Taiwan	0.5–1	Adults	Areca nut with betel leaf
Migrant populations (UK, Middle East, USA)	0.2–0.5	South Asian diaspora	Imported gutka and supari

The panel noted that the disease exemplifies the intersection of cultural practices, trade globalisation, and non-communicable disease epidemiology. KR advocated for national policies mirroring the WHO Framework Convention on Tobacco Control (FCTC), including taxation, advertising bans, pictorial warnings, and prohibiting sales near schools. There was a unanimous consensus that urgent regulatory and preventive interventions are necessary to curb the rising burden.

Final Consensus Statement: OSMF is a global oral health priority, strongly linked to areca nut consumption, with no safe threshold of use. Urgent public health action, including taxation, sales restrictions, and awareness campaigns, is necessary, with a particular focus on protecting young people.

Pathogenesis and molecular insights

The pathogenesis of OSMF is multifactorial, with the consensus that the areca nut, and its alkaloid arecoline remain the central drivers. Laboratory studies have confirmed that arecoline triggers fibroblast activation, increases procollagen synthesis, and impairs collagen degradation.[16] The TGF-β signalling pathway was identified by the panel as the dominant molecular mechanism perpetuating fibrosis [Figure 5].

Figure 5.

Integrated pathogenesis and management framework of oral submucous fibrosis

RR provided evidence of host susceptibility factors, particularly polymorphisms in cytokine genes (e.g. TNF-α and IL-6) and detoxification enzymes (GSTs and CYPs). These genetic variations, RR argued, partly explain why some heavy chewers never develop OSMF, whereas others progress rapidly. PA highlighted the role of EMT, noting that fibroblast heterogeneity contributes to fibrosis persistence. Her research on gingival fibroblasts revealed increased collagen synthesis and resistance to apoptosis, which is consistent with a ‘fibrosis-prone phenotype’. KD brought in translational relevance from the perspective of senescence biology. KD presented data showing that senescent fibroblasts in OSMF exhibit a senescence-associated secretory phenotype (SASP) that promotes inflammation and fibrosis. KD proposed senolytics and secretum-modifying therapies as potential novel interventions. The panel also discussed systemic parallels. WMT focused on similarities with idiopathic pulmonary fibrosis and hepatic fibrosis, suggesting that OSMF could serve as a unique oral model for fibrosis–carcinogenesis transition research [Figure 6].

Figure 6.

Pathogenesis of oral submucous fibrosis and malignant transformation

Final Consensus Statement: The pathogenesis of OSMF is driven by arecoline-mediated fibroblast activation through TGF-β signalling, with genetic, oxidative, EMT, and senescence-related factors contributing. OSMF shares mechanisms with systemic fibroses, highlighting opportunities for translational research[17] [Table 3].

Table 3.

Molecular and cellular mechanisms in oral submucous fibrosis

Mechanism	Key evidence	Panellists
TGF-β signalling	Overexpression → collagen deposition	RR
Fibroblast heterogeneity	Persistent activation, resistance to apoptosis	PA
EMT	Upregulation of Snail, Twist, and vimentin	PA
Genetic polymorphisms	IL-6, TNF-α, GST, CYP variants	RR
Senescence and SASP	Pro-fibrotic inflammatory microenvironment	KD
Oxidative stress	ROS-induced DNA damage	Consensus

OSMF=Oral submucous fibrosis, TGF-β = Transforming growth factor-beta, EMT=Epithelial–mesenchymal transition, IL-6=Interleukin-6, TNF-α = Tumor necrosis factor-alpha, GST=Glutathione S-transferase, CYP=Cytochrome P450, SASP=Senescence-associated secretory phenotype, ROS=Reactive oxygen species, DNA=deoxyribonucleic acid

Clinical features and diagnostic criteria

A consensus was reached that the OSMF diagnosis should combine functional limitations with mucosal features. Early stages present as a burning sensation, intolerance to spicy foods, and diffuse blanching. Advanced cases show palpable fibrous bands, mucosal rigidity, and trismus with an inter-incisal distance often <35 mm. VH emphasised the importance of community-based screening, proposing simplified protocols that can be used by primary care physicians and dentists. He argued that ‘every case of trismus in South Asia should raise the suspicion of OSMF until proven otherwise’.[18]

On histopathology, a consensus was reached that evaluation should incorporate both fibrosis severity and epithelial dysplasia. WMT highlighted that dysplasia in OSMF may not resemble conventional leukoplakia-associated dysplasia, often presenting with atrophic epithelium and atypical basal changes. WMT strongly advocated for the development of an OSMF-specific dysplasia grading system to avoid underestimating malignant potential.[19]

PR, emphasising habit cessation, early screening, and personalised medicine, was consistently reinforced through targeted questions—particularly regarding genetic susceptibility markers, EMT, and the ethical risks of repurposing areca nut for the treatment of cognitive disorders such as Alzheimer’s disease. PR warned against the therapeutic misappropriation of a known carcinogen, especially among geriatric populations vulnerable to misinformation, and unregulated alternative medicine practices. PR also introduced clinical provocations that deepened the panel’s exploration of gene-environment interactions, most notably the case of a 6-year-old child diagnosed with OSMF, despite long-standing areca use in asymptomatic adult family members. This case highlights the urgency of early genetic screening, paediatric surveillance, and context-sensitive public health education.[20]

There is also agreement that longitudinal monitoring is essential. This includes serial functional measurements, photographic documentation, and repeat biopsies in patients with persistent or progressive changes.

Final consensus statement

The diagnosis of OSMF should be based on functional limitations and mucosal changes, with histopathology incorporating fibrosis and dysplasia [Table 4]. The development of an OSMF-specific dysplasia grading system is recommended. Longitudinal monitoring is mandatory.

Table 4.

Clinical and histopathological features of oral submucous fibrosis

Stage	Clinical features	Histopathological features
Early	Burning, blanching, mucosal erythema	Juxta-epithelial inflammation, mild fibrosis
Moderate	Fibrous bands, trismus (<35 mm), mucosal rigidity	Hyalinized collagen, epithelial atrophy
Advanced	Severe trismus (<20 mm), inability to protrude the tongue	Dense fibrosis, epithelial dysplasia, vascular reduction

OSMF=oral submucous fibrosis

Management approaches

The consensus was strong that habit cessation is the cornerstone of management. Without eliminating areca nut use, all pharmacological and surgical interventions are temporary. KR emphasised integrating addiction biology into management, advocating for specialised cessation clinics that combine behavioural counselling, pharmacological aids, and community outreach. For pharmacological interventions, corticosteroids (topical and intralesional), antioxidants (lycopene), COX-2 inhibitors, and antifibrotics (such as pentoxifylline) are useful in early to moderate disease. However, the panel agreed that evidence is variable, and that the benefits are primarily symptomatic (improved burning, modest increase in mouth opening).[21] Surgical interventions were supported for advanced cases with trismus. Buccal fat pad grafting, collagen sheets, and PRF/platelet-rich plasma (PRP) applications were highlighted as beneficial, significantly improving mouth opening. However, recurrence remains common without habit cessation.[22] Emerging therapies have generated considerable discussion. KD highlighted regenerative therapies, including stem cell–derived secretomes and senolytics, whereas others noted the potential of photobiomodulation. The consensus was that while promising, these approaches remain experimental and require multicentre randomised trials before mainstream adoption.[23]

Final consensus statement

Management of OSMF requires habit cessation as first-line therapy, with pharmacological treatments in early disease, surgical interventions for advanced trismus, and emerging therapies as prospects [Table 5].

Table 5.

Management options in oral submucous fibrosis

Approach	Indication	Evidence strength	Notes
Habit cessation	All cases	Strong	Essential for success
Corticosteroids	Early–moderate	Conditional	Symptom relief
Antioxidants (lycopene, curcumin)	Early–moderate	Conditional	Reduce oxidative stress
COX-2 inhibitors	Symptomatic	Conditional	Anti-inflammatory
Surgery (fibrotomy, grafting)	Severe trismus	Strong	Improves function
PRF/PRP adjuncts	Surgical cases	Conditional	Promising regenerative effect
Emerging therapies (stem cell secretome, senolytics, PBM)	Clinical trials	Conditional	Require multicentre validation

OSMF=oral submucous fibrosis, COX-2=Cyclooxygenase-2, PRF=Platelet-rich fibrin, PRP=Platelet-rich plasma, PBM=Photobiomodulation

Malignant transformation and oncological considerations

The malignant potential of OSMF has been unanimously acknowledged. Systematic reviews indicate a transformation rate of 4%–7%, making it one of the highest-risk OPMDs. The panel agreed that all OSMF patients require lifelong surveillance. WMT emphasized that OSCC arising in OSMF exhibits distinct characteristics: it tends to be exophytic, shows reduced nodal metastasis, and develops against a background of dense fibrosis[24] [Figures 7 and 8]. WMT advocated for a modified TNM staging system for OSMF-associated OSCC to enhance prognostication. The panel also discussed oncological management. While standard OSCC protocols are used, differences in tumour biology may necessitate tailored approaches in surgical margins, lymph node management, and adjuvant therapy.[25]

Figure 7.

Bar plot summarising key insights into Oral Submucous Fibrosis (OSMF). This multi-panel figure highlights critical epidemiological, molecular, clinical, and translational aspects of OSMF. (a) Regional prevalence (%): The highest burden is observed in the northeastern and eastern regions of India, followed by Kerala and South India (Karnataka/Andhra Pradesh). (b) Areca nut forms and OSMF risk: Risk is highest with raw green nut, gutka, and combined nut + lime + tobacco, compared with boiled or sun-dried forms. (c) Key genes linked to OSMF: Genetic susceptibility involves HLA, TGF-b1, IL-6, TNF-a, CYPs, GSTs, XRCC, and regulatory miRNAs. (d) OSMF treatment spectrum: Management spans lifestyle modification and counselling, pharmacological therapy, minimally invasive procedures, surgical interventions, and advanced reconstructive approaches. (e) OSCC in OSMF vs. conventional cases: Feature scores demonstrate lower nodal spread, invasion, and improved prognosis in OSMF-associated oral squamous cell carcinoma than in conventional OSCC. (f) Future research areas: Priority domains include genomics, stem cell therapy, senolytic interventions, photobiomodulation (PBM), epithelial–mesenchymal transition (EMT) biology, and animal model development. OSMF = Oral submucous fibrosis, OSCC = Oral squamous cell carcinoma

Figure 8.

Comparison of OSMF-associated OSCC versus conventional OSCC. OSMF = Oral submucous fibrosis, OSCC = Oral squamous cell carcinoma

Final consensus statement

OSMF has a malignant transformation risk of 4%–7% and requires lifelong surveillance. OSCC arising from OSMF is biologically distinct and may require modified staging and tailored oncological management [Table 6].

Table 6.

Malignant transformation in oral submucous fibrosis

Parameter	Evidence
Malignant transformation rate	4%–7%
Cancer type	Oral squamous cell carcinoma (OSCC)
Distinct clinical features	Exophytic growth, reduced nodal spread
Histological features	Dense fibrosis, atypical basal epithelium
Prognostic implications	Need for modified TNM staging

OSMF=oral submucous fibrosis, OSCC=oral squamous cell carcinoma, TNM=tumour, node, metastasis

Policy and preventive strategies

The consensus was strong on the need for robust public health policies. KR argued for adopting a framework analogous to the WHO-FCTC for areca nut, including taxation, plain packaging, advertising bans, and sales prohibition near schools [Table 7]. The panel also agreed on the establishment of centres of Excellence for OPMDs, which would serve as referral hubs for diagnosis, treatment, training, and research. Such centres would also coordinate surveillance programs and facilitate international collaborations.

Table 7.

Recommended policy measures for oral submucous fibrosis control

Strategy	Example	Global relevance
Taxation	Higher excise duty on gutka/pan masala	India, Bangladesh
Advertising bans	Ban on TV/radio ads	Sri Lanka, Nepal, India
Packaging warnings	Pictorial warnings	Taiwan, India
Sales restrictions	Prohibition near schools	Proposed globally
Centres of Excellence	Specialised OPMD clinics	Recommended by the panel

OSMF=oral submucous fibrosis, OPMD=oral potentially malignant disorder

Final consensus statement

Governments must formally recognise OSMF as a precancerous, irreversible disorder and integrate it into non-communicable disease programs. Strict regulation of areca nut products and establishment of Centres of Excellence are urgently needed.

DISCUSSION

The present consensus statement represents the first WHO-aligned, multidisciplinary effort to consolidate diagnostic, therapeutic, and public health strategies for OSMF, a chronic, irreversible, and potentially malignant disorder with alarming global implications.[26] By integrating expert opinions, systematic evidence synthesis, and structured consensus-building, this guideline provides a unified framework to address the challenges of OSMF across clinical, molecular, and public health domains.

While OSMF has long been endemic to South Asia, particularly India, Sri Lanka, Nepal, and parts of Southeast Asia, emerging data suggest global epidemiological expansion.[27] The migration-driven dissemination of areca nut products has contributed to the increasing incidence of OSMF in diaspora-rich countries such as the UK, UAE, and Pacific Islands, which lack adequate surveillance or prevention strategies. Our consensus reinforces the need for global disease recognition, including the incorporation of OSMF within the WHO’s oral health monitoring frameworks and national NCD (non-communicable disease) registries.[28]

The consensus strongly emphasised the Group 1 carcinogenicity of areca nut, independent of tobacco. Although public perception often minimises the risk of ‘plain supari’, molecular studies have shown that arecoline and polyphenols induce profibrotic cascades via TGF-β, Smad2/3, and reactive oxygen species (ROS)-mediated DNA damage.[29] Several panellists, including VH and RR, stressed that habit modification campaigns must target cultural myths, socioeconomic vulnerabilities, and peer-driven behaviour, particularly among youth and female users, who remain underdiagnosed.[30]

The traditional understanding of OSMF as a fibrosis-centric condition is now augmented by emerging insights into EMT, cellular senescence, and immune dysregulation. Our panel underscores the translational parallels between OSMF and systemic fibrotic conditions such as idiopathic pulmonary fibrosis and hepatic cirrhosis, offering a model to understand the fibrosis–carcinoma continuum.[31] Moreover, KD highlighted how senolytics and omics-informed drug repositioning could pioneer next-generation therapies.

A critical gap identified was the lack of uniform clinical diagnostic thresholds. The traditional reliance on interincisal opening does not adequately capture early fibrotic or epithelial changes. WMT’s proposal for a refined histopathological grading system tailored to OSMF-associated dysplasia has been widely endorsed.[32] Surveillance protocols should integrate photographic documentation, clinical scoring, and repeat biopsy protocols, particularly in patients with atypical features or high-risk molecular profiles.[33]

While corticosteroids, hyaluronidases, and antioxidants remain the mainstays in early-to-moderate cases, evidence supporting their long-term efficacy remains limited. The consensus recommends tailored regimens that combine pharmacologic and surgical approaches with habit cessation as a mandatory prerequisite.[34] In advanced trismus, buccal fat pad grafting, PRF, and regenerative scaffolds have shown promise, although more longitudinal data are needed. Future directions include stem cell-derived exosomes, COX-2 modulators, and senescence-targeting therapies.[35]

The estimated malignant transformation rate of 4%–7%, as agreed upon by the panel, mandates lifelong follow-up. OSMF-associated OSCC is clinically distinct—often presenting with reduced nodal spread, stromal stiffness, and exophytic growth. Prof. Tilakaratne’s call for TNM staging modifications to reflect this unique biology was well received. There is an urgent need for molecular risk stratification tools (e.g. p53, podoplanin, miRNA panels) to guide surveillance and treatment.[24]

The consensus panel strongly endorsed WHO-style public health interventions for OSMF, modelled on the FCTC. The recommended measures include areca nut taxation, the introduction of pictorial health warnings, the prohibition of sales near schools, and the banning of flavoured formulations that particularly target youth. KR emphasised the necessity of intersectoral collaboration, engaging ministries of health, education, food safety, and legal authorities, to create a cohesive framework for areca nut regulation.[36] Furthermore, the panel proposed establishing regional Centres of Excellence for OPMDs, which would act as referral hubs for diagnosis, research, clinical training, and surveillance.[37]

The strength of this consensus lies in its methodological rigour, which includes a multidisciplinary steering committee, transparent Delphi-style voting, and explicit documentation of divergent viewpoints. Clear expert attribution further enhances academic accountability and recognition. However, the process faced limitations such as the absence of direct patient representation, limited high-quality randomised controlled trials to validate emerging therapies, and underrepresentation of perspectives from regions such as Africa and Latin America. The panel therefore recommends adopting a ‘living guideline’ model for future updates, integrating new evidence in real time and expanding stakeholder participation to include patients, caregivers, and policymakers.

CONCLUSION

This WHO-style consensus guideline on OSMF consolidates evidence and expert opinion into actionable recommendations for diagnosis, management, and prevention. By prioritising habit cessation, standardised care, and public health regulation, it provides a global framework to reduce disease burden and malignant transformation, aligning with broader WHO non-communicable disease strategies.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.