Challenges in the Classification of Oral Submucous Fibrosis and Proposing a New Classification Based on Systematic Review of Literature

ABSTRACT

Aims and Objectives:

Oral submucous fibrosis is one of the common oral potentially malignant disorders that can result in severe morbidity. Due to its widespread involvement in the oral cavity and high risk of malignant transformation, the diagnosis and treatment of this disease at an early stage is essential to prevent further complications. This research was carried out to review various classification systems of oral submucous fibrosis documented in the literature to date, including their benefits and drawbacks, thus focusing on a need to discover some reliable classification systems.

Materials and Methods:

An electronic search of the published English literature was performed without publication year limitation in PubMed/Medline, Science Direct, Web of Science, Google Scholar, and Scopus databases using keywords like (‘Oral submucous fibrosis’ OR ‘Oral submucous fibroses’), AND (‘Classification’ OR ‘Grade’ OR ‘Stage’), AND (‘Clinical’, OR/ AND ‘Histological’, OR/AND ‘Functional’) following PRISMA guidelines. A manual search of all related Dental and Medical journals was also performed. We also checked the reference lists of the relevant articles for any other possible information on the subject.

Results:

The search strategy revealed 31 relevant articles and it could be appreciated that oral submucous fibrosis has been classified in seven different ways. Each system is enclosed with its own limitations and benefits.

Conclusion:

From this research, it can be concluded that despite the existence of several classification systems for oral submucous fibrosis, at present, no classification scheme is considered to be reliable that could help in the accurate assessment of the progression of the disease and classifying oral submucous fibrosis still remains a challenging task for clinicians, surgeons, and pathologists. We have postulated a proposed new classification system based on our literature research, but still robust research is needed in this aspect.

BACKGROUND

Oral submucous fibrosis (OSMF) is one of the common oral potentially malignant disorders (OPMDs) that can result in severe morbidity. World Health organization (WHO) Collaborating Centre for Oral Cancer in the UK in March 2020 redefined OSMF as “a chronic, insidious disease that affects the oral mucosa, initially resulting in loss of fibro elasticity of the lamina propria and as the disease advances, results in fibrosis of the lamina propria and the submucosa of the oral cavity along with epithelial atrophy”[1]

OSMF is a disease of multifactorial etiology; Areca nut (AN) being the major etiological agent. Other contributory factors include smokeless tobacco, chilies, nutritional impairments, genetics, autoimmunity, and infections.[2] The condition mostly affects the Southeast Asia region because of the increased prevalence of AN chewing habits.[3] According to WHO, >5 million people are affected by OSMF globally.[4] It can involve any age group with more involvement of young to middle age and a female predilection, although some studies reveal the male predominance.[5,6] It has been found even in the pediatric patients and the school-going children too.[7]

Clinically, OSMF is characterized by the symptoms such as burning sensation (BS), vesicle formation, ulceration, pain, loss of pigmentation, leathery texture of the oral mucosa (OM), blanching, marble like appearance, reduced tongue movement, progressive reduction of mouth opening (MO), and sunken cheeks, fibrous bands (FB) in the buccal mucosa (BM) and other sites resulting in trismus, speech and deglutition defects, shrunken uvula, and further showing the evidence of premalignant and malignant changes in the OM.[4]

Histopathologically, OSMF is characterized by marked epithelial atrophy, loss of rete pegs, and subepithelial hyalinization with abnormal excessive collagen deposition leading to abundant fibrosis and muscle degeneration. Epithelium may show dysplastic changes signifying the high-risk malignant transformation of this condition.[4]

It has been suggested that the derivatives of AN, such as arecoline and nitrosamines, can induce neoplastic changes in the OM of OSMF patients.[8] As compared to other OPMDs, which exhibit increasing grade of epithelial dysplasia and increased angiogenesis while getting transformed into malignancy, OSMF progresses as a fibrotic state associated with reduced vasculature which at a critical juncture shall likely to reverse to an increased angiogenesis, marking the potential for a malignant transformation. This unique behavior is often too hard to follow up which is a major reason why it is difficult to predict if a OSMF will turn malignant or not.

Because of its widespread involvement in the oral cavity and high-risk of malignant transformation, the diagnosis and treatment of this disease at an early stage to prevent further complications are essential. The degree of progression of the disease is assessed by its grading/staging. The treatment plan varies according to the stage/grade of the disease. Early stages can be managed through nutritional and medicinal approaches, whereas the moderately advanced stages need surgical management.[9] Various scholars have attempted to propose different classification systems of OSMF depending on variable parameters. But till now, no reliable system is available for the accurate staging/grading of OSMF, and the classification of this disease remains a challenging task for the clinicians, surgeons, and pathologists. This research aims to review various classification systems of oral submucous fibrosis documented in the literature to date, including their benefits and drawbacks, thus focusing on the need to discover some reliable classification system.

MATERIALS AND METHODS

This review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Considering the nature of the current review, there was no necessity of taking any ethical approval.

FOCUSED PICO QUESTION

For screening the relevant search, we defined a Population, Intervention, Comparison, Outcome (PICO) question; ‘‘How many classification systems of OSMF are listed in the literature to date, and which system is the most reliable?”

1. Population: OSMF patients;

2. Intervention: Classification systems;

3. Comparison: Between different classification systems for OSMF;

4. Outcome: Benefits and drawbacks of different classification systems of OSMF.

SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES

An electronic search of the published literature was performed without publication year limitation in PubMed/Medline, Science Direct, Web of Science, Google Scholar, and Scopus databases using keywords like (‘Oral submucous fibrosis’ OR ‘Oral submucous fibroses’), AND (‘Classification’ OR ‘Grade’ OR ‘Stage’), AND (‘Clinical’, OR/ AND ‘Histological’, OR/AND ‘Functional’) following PRISMA guidelines. A manual search of all related Oral pathology, Maxillofacial, Dental, and Medical journals was also performed. We also checked the reference lists of the relevant articles for any other possible information on the subject [Figure 1].

Figure 1.

PRISMA flowchart showing search strategy and study screening

SCREENING OF STUDIES

The current review involved three steps of screening the studies. In the first step, titles were reviewed by two authors (SG, ASu) independently and duplicates were removed. Then the other four authors (SS, PS, AS, AK) reviewed the selected abstracts of all the reports independently. If the title/abstracts met the eligibility rule, they were included in the study. In the final stage, the text of selected studies was screened by all authors (SG, ASu, SS, PS, AS,AK, HS, KTN) separately. separately. The full report was collected, discussed, and resolved for cases among all authors that appeared to fit the inclusion criteria or for which evidence was insufficient to make a clear determination.

INCLUSION CRITERIA

• Articles presenting various classification systems of OSMF in the literature published till the present.

• Case studies, epidemiological studies, cross-sectional studies, and clinicopathological studies conducted on OSMF, in which researchers have proposed their own classification system.

• Articles published in the English literature only.

EXCLUSION CRITERIA

• Articles with incomplete data.

• Classifications repeated in different studies were excluded.

• Papers focusing only on grading of epithelial dysplasia in OSMF were excluded.

• Articles with incomplete data. Classifications repeated in different studies were excluded.

• Papers focusing only on the grading of epithelial dysplasia in OSMF were excluded.

• Abstracts, editorials, letters, correspondences, web pages, media files, and book chapters.

RISK OF BIAS ASSESSMENT

The risk of bias in the included studies was appraised following Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklists. Almost in all papers, the required information was available, except in a few. We tried reaching the authors of those cases to clarify this bias; however, we were unable to recover the missing information. We didn’t include those papers in our study.

DATA EXTRACTION

The titles and abstracts of all articles identified were read independently by the authors. Any discrepancy for the insufficient data and inaccurate selection of the articles was discussed, and resolved. The data were then extracted after careful evaluation. Data points obtained from the literature review included authors’ names and year of publication, and the classification proposed. Data extracted were tabulated, cross-checked, and summarized [Tables 1,2,3,4,5,6–7].

Table 1.

Classification of oral submucous fibrosis based on clinical parameters (Ref [10,11,12,13,14,15,16,17,18])

Author (year)	Criteria used	Classification
Desa JV (1957)	Features such as the presence of vesicles, stomatitis, FB and the evidence of other pre-malignant and malignant changes in the OM.	Stage I: Stomatitis and vesiculation. Stage II: Fibrosis. Stage III: Sequelae of the disease.
Wahi PN et al. (1966)	Clinical features, severity and the extent of involvement of the oral cavity.	Group I: No symptoms related to BM, localized pallor/whitish discoloration of the OM. Group II: Soreness of the OM, hypersensitivity to capsaicin, diffuse white extensive lesions. Group III: Firm FB, ulcerated/ fissured mucosa, trismus, speech defect.
Ahuja SS and Agarwal GD (1971)	Extent and the severity of fibrosis.	Class I: FB in the BM involving superior and inferior vestibular fornixes on both sides. Class II: Generalized FB involving BM, HP, SP, uvula and the FP, involvement of pharynx. Class III: Combination of above 2 classes.
Bhatt AP and Dholakia LM (1971)	Symptoms of disease, amount of fibrosis present and the ability of MO.	Grade I: Mild symptoms, very less amount of FB and normal MO. Grade II: Moderately pronounced symptoms, FB extending posteriorly towards palate, reduced MO. Grade III: Marked FB on BM, LM, palate, uvula, tongue and restricted MO.
Gupta DS et al. (1980)	Extent of symptoms, amount of fibrosis and the patient’s ability of MO.	Stage 1: Very early BS or ulceration with normal MO. Stage 2: Early BS with slight difficulty in MO. Stage 3: Moderately advanced Marked trismus, extensive reduced MO, difficulty in mastication. Stage 4: Advanced Undernourishment, anemia and marked degree of trismus.
Pindborg JJ (1989)	Both intraoral and extraoral symptoms	Stage I: Early Stomatitis, erythema, vesiculation, ulceration, melanotic pigmentation, and petechiae. No significant extraoral features. Stage II: Moderate Features of stage 1 along with fibrosis in ruptured vesicles and ulcers while healing, blanching of the OM and FM, palpable FB in the BM, LM, mottled marble like appearance of the OM, gradual reduction of the MO (trismus), stiff and small tongue, fibrotic and depigmented gingiva, rubbery SP, blanched and atrophied tonsils, shrunken budlike uvula. Prominent masseter, nasal twang, sunken cheeks, thin lips, difficulty in deglutition, obliterated naso-labial fold, prominent ante gonial notch, hoars voice, hearing defects, weight loss. Stage III: Advanced Any of the above features along with precancerous and cancerous lesions and conditions such as LP/ EP/ OSCC. Severe hearing defects, severe weight loss, hoarse voice, difficulty in deglutition, atrophied facial muscles. Altered condyle and fibrous ankylosis of the TMJ evident on radiograph.
Mathur RM and Jha T (1993)	Symptoms, MO, CF, FB.	Stage I:- Early Mild blanching, BS, normal MO, normal tongue movements, normal CF. Stage II:- Moderate Moderate to severe blanching, BS, 33% reduction in MO, reduced CF, palpable FB, lymphadenopathy, anemia. Stage III:- Severe Severe BS, >66% reduction in MO, CF, tongue protrusion, ulceration in BM, thick palpable FB, bilateral lymphadenopathy.
Mehar R et al. (1996)	Extent of involvement of oral cavity. (Divided entire oral cavity into eight regions anatomically; palate, posterior 1/3rd of BM, middle 1/3rd of BM, anterior 1/3rd of BM, maxillary LM, mandibular LM, tongue and FM).	Group A: <1/3rd of the oral cavity involved Group B: 1/3rd to 2/3rd of the oral cavity involved. Group C: >2/3rd of the oral cavity involved.
Ranganathan K et al. (2001)	Symptoms and MO.	Group I: Only symptoms, with normal MO. Group II: MO 20 mm and above. Group III: MO < 20 mm. Group IV: Limited MO. Precancerous or cancerous changes seen throughout the OM.
Rajendran R et al. (2003)	Clinical symptoms.	Early stage: BS, blisters on the palate, ulcers or generalized inflammation of the OM, excessive salivation, defective taste and dry mouth. Advanced stage: Blanched and opaque OM, FB in BM running towards the palate and FP, impairment of the tongue movement and difficulty in MO.
Bose T and Balan A (2007)	Symptoms, extent of MO, tongue movement and FB.	Mild stage: Pallor, vesicle formation, palpable FB, loss of elasticity of mucosa, variable tongue involvement, >3 cm MO. Moderate stage: Soreness, hypersensitivity to chillies, blanching, palpable FB, variable tongue movements, MO 1.5-3 cm. Severe stage: More severe symptoms, broad FB, blanched opaque OM, restricted tongue movement, MO<1.5cm, depapillated tongue.
Tupkari JV et al. (2007)	Symptoms, FB, MO, Tongue movements.	Grade I: (Incipient/ Very early stage) BS, dry mouth, vesicles, ulceration, irritation by spicy food, normal color of OM, no palpable FB, normal tongue protrusion, normal MO. Grade II: (Mild/ Early stage) BS, dry mouth, irritation by spicy food, blanched OM, no palpable FB, normal tongue protrusion, slight restriction of MO. Grade III: (Moderate/ Moderately advanced stage) BS, dry mouth, irritation by spicy food, blanched, opaque, leather-like OM, vertical palpable FB on BM, normal tongue protrusion, more restriction of MO, difficulty in eating and speaking, poor oral hygiene. Grade IV: (Severe/ Advanced stage) BS, dry mouth, irritation by spicy food, blanched, opaque, leather-like OM, vertical palpable FB in entire oral cavity, restricted tongue protrusion, very little MO, much impaired eating and speech, very poor oral hygiene.
Aziz SR (2008)	Clinical features and the extent of MO	Group 1: Early disease (MO >35mm) Group 2: Mild to moderate disease (MO 26-35mm) Group 3: Moderate to severe disease (MO 15-25 mm) Group 4a: Severe disease (MO <15 mm) Group 4b: Extremely severe, malignant/ premalignant changes seen.
Mehrotra D et al. (2009)	Symptoms, amount of fibrosis and the degree of MO.	Grade 1: Stomatitis/ vesiculation, BS, no fibrosis. Grade 2: Symptoms of grade I, palpable FB, involving SP, MO 26-35mm. Grade 3: Symptoms of grade 2, blanched OM, involving tongue & MO is 6-25mm. Grade 4: Symptoms of grade 3, fibrosis of lips & MO is 0-5mm.
Kerr RA et al. (2011)	Clinical symptoms and the range of MO.	Stage 1: Mild Any features of the disease (BS, depapillation, blanching or leathery OM) and MO >35 mm. Stage 2: Moderate Above features + MO 20–35 mm. Stage 3: Severe Above features + MO < 20 mm. Stage 4A: OSMF + other potentially malignant disorder evident clinically. Stage 4B: OSMF with any grade of OED on biopsy. Stage 5: OSMF with features of OSCC.

BM = buccal mucosa, BS = burning sensation, CF = cheek flexibility, EP = erythroplakia, FB = fibrous bands, FM = floor of the mouth, HP = hard palate, IID = interincisal distance, LM: labial mucosa, LP = leukoplakia, MO = mouth opening, OED = oral epithelial dysplasia, OM = oral mucosa, OSMF = oral submucous fibrosis, OSCC = oral squamous cell carcinoma, PRMO = percentage of reduction in mouth opening, SP = soft palate, TMJ = temporomandibular joint

Table 2.

Classification of oral submucous fibrosis based on functional parameters (Ref-[17,18,19,20,21,22,23])

Author (year)	Criteria used	Classification
Katharia SK et al. (1992)	MO	Score 0: >41 mm MO Score 1: 37-40 mm MO Score 2: 33-36 mm MO Score 3: 29-32 mm MO Score 4: 25-28 mm MO Score 5: 21-24 mm MO Score 6: 17-20 mm MO Score 7: 13-16 mm MO Score 8: 9-12 mm MO Score 9: 5-8 mm MO Score 10: 0-4 mm MO
Lai DR (1995)	MO	Group A: > 35mm MO. Group B: 30-35 mm MO. Group C: 20-30 mm MO. Group D: < 20 mm MO.
Kumar K (2007)	MO	Stage I: > 45 mm MO. Stage II: 20-44 mm MO. Stage III: < 20 mm MO.
Hazarey VK et al. (2007)	MO	Grade I: 40-49 mm MO. Grade II: 30-39 mm MO. Grade III: 20-29 mm MO. Grade IV: 10-19 mm MO. Grade V: 0-9 mm MO.
Patil S and Maheshwari S (2014)	CF	Grade 1: Early 30 mm and above CF Grade 2: Mild 20 to 30 mm CF Grade 3: Moderate < 20 mm CF Grade 4: Severe Any of the above grades without evident potential malignant lesions. Grade 5: Advanced Any of the above conditions with evident malignant lesions.
Nanavati S et al. (2015)	IID	Stage 1: Very early stage IID = >3.50 cm Stage 2: Early stage IID = 2.5-3.5 cm Stage 3: Moderately advanced stage IID = 1.5-2.5 cm Stage 4: Advanced stage IID = <1.5 cm
Hameed KS et al. (2019)	First graded the disease according to Haider et al. system and histologically, according to Pindborg and Sirsat’s criteria. Then they had measured normal MO using TFI and recorded the existing MMO. And, finally assessed the PRMO by subtracting the MMO from the TFI and proposed a new staging system.	Stage I : < 30% PRMO Stage II: 30-45% PRMO Stage III: >45% PRMO

CF = cheek flexibility, IID = interincisal distance, mm = millimeters, MO = mouth opening, MMO = maximum mouth opening, PRMO = percentage of reduction in mouth opening, TFI = three finger index

Table 3.

Classification of oral submucous fibrosis based on clinical & functional parameters (Ref [24,25])

Author (Year)	Criteria used	Clinical staging	Functional staging
Haider et al. (2000)	Association of FB and the range of MO.	Stage 1: Presence of faucial FB only. Stage 2: Faucial and buccal FB. Stage 3: Faucial and labial FB.	Stage A: 13-20 mm MO. Stage B: 10-11 mm MO. Stage C: <10 mm MO.
More CB et al. (2011)	Association of clinical features and MO.	S1: Stomatitis and/or blanching of OM. S2: FB in BM and/or oropharynx, with/without stomatitis. S3: FB in BM and/or oropharynx, any other parts of oral cavity, with/without stomatitis. S4A: Any of the above stage with potentially malignant disorders such as EP, LP. S4B: Any of the above stage with OSCC.	M1: >35mm MO. M2: 25-35 mm MO. M3: 15-25 mm MO. M4: <15 mm MO. Staging is given as S1M1, S1M2 etc.

BM = buccal mucosa, EP = erythroplakia, FB = fibrous bands, LP = leukoplakia, MO = mouth opening, OM = oral mucosa, OSCC = oral squamous cell carcinoma

Table 4.

Classification of oral submucous fibrosis based on histopathological parameters. (Ref [18,19,26])

Author (year)	Criteria	Stage	Features
Pindborg JJ and Sirsat SM (1966)	Based on histological changes.	Very early	Fine CF, large no. of fibroblasts, dilated and congested BV, marked edema, inflammatory infiltrate mainly neutrophils and eosinophils.
		Early	Thick CF, early JEH, moderate no. of fibroblasts, dilated and congested BV, less edema, inflammatory infiltrate mainly eosinophils, lymphocytes and plasma cells.
		Moderately advanced	Dense CF, moderate JEH, less no. of fibroblasts, fibrocytes with elongated spindle shaped nuclei and scant cytoplasm, normal or constricted BV, decreased vascularity, slight edema, inflammatory infiltrate mainly lymphocytes and plasma cells, few eosinophils.
		Advanced	More dense bundle of CF, Completely hyalinized, extending into the submucosa replacing fat or fibrovascular tissue, inflammation of minor salivary glands and muscle degeneration, tissue fibrosis, fibroblasts absent, completely obliterated BV, absence of edema, inflammatory infiltrate mainly lymphocytes and plasma cells.
Utsunomiya H et al. (2005)	Used Pindborg’s criteria and modified the classification.	Early	Abundant lymphocytes in subepithelial CT region along with myxedematous changes.
		Intermediate	Reduced inflammatory cells in the subepithelial layer, subepithelial hyalinization, compressed BV, fibrous bundles, granulation changes close to the muscle layer.
		Advanced	Inflammatory cell infiltrate hardly seen, hyaline changes extending towards subepithelial muscle layers, marked fibrosis, small BV, atrophic and degenerative changes start in the muscle fibers.
Kumar KK (2007)	Characteristics of CF.	I	Loose, thick & thin CF.
		II	Loose or thick CF with partial hyalinization.
		III	Complete hyalinization.

BV = blood vessels, CF = collagen fibers, CT = connective tissue, JEH = Juxta epithelial hyalinization

Table 5.

Classification of oral submucous fibrosis based on clinical and histopathological parameters[17,27]

References	Criteria	Category	Clinical classification	Histopathological classification
Khanna JN and Andrade (1995)	Clinical and histological features.	Group I	Early stage Normal MO, BS, ulceration, stomatitis.	Thin collagen fibers, marked edema, dilated and congested BV, large aggregate of plump, young fibroblasts with rich cytoplasm, inflammatory cells mainly neutrophils with few eosinophils, epithelium is normal.
		Group II	Moderate stage MO 26–35 mm. mottled, marble like BM, widespread fibrosis.	Thick bundles of CF, JEH, dilated and congested BV, moderate number of young fibroblasts, Inflammatory cells mainly neutrophils, eosinophils and plasma cells, Flat rete ridges with varying degree of keratinization.
		Group III	Moderately advanced stage MO 15–26 mm. trismus, pale and firm BM, FB at the SP, pterygomandibular raphe and anterior FP.	Thick bundles of CF, JEH, congested BV, mature fibroblasts with scant cytoplasm and spindle shaped nuclei, inflammatory component mainly lymphocytes and plasma cells, flat rete ridges with varying degree of atrophy, muscle fibers interspersed with thick and dense CF.
		Group IV	Advanced stage A: MO <15 mm, Severe trismus, and extensive fibrosis of entire OM, thickened FP, shortened and firm to palpation, shrunken bud like fibrous uvula, limited tongue movements, circular bands around entire mouth. B: Premalignant and malignant changes throughout the OM.	Hyalinized collagen, extensive fibrosis, obliterated BV, markedly absent fibroblasts. extensive muscle degeneration, loss of rete ridges, epithelium shows mild to moderate atypia.
Rajinikanth et al. (2016)	Based on the review of previously proposed classifications.	Stage I	BS, altered taste, no symptoms related to BM, 36–40 mm MO.	Fine CF, marked oedema, plump young fibroblasts, inflammatory infiltrate mainly lymphocytes and plasma cells, normal epithelium.
		Stage II	BS, hypersensitivity to spicy food, FB on any region of OM, 32–36 mm MO.	Thick bundles of CF, moderate number of young fibroblasts, inflammatory infiltrate mainly lymphocytes and eosinophils, flat rete ridges, varying degree of keratinization.
		Stage III	Severe BS especially on hot and spicy consumption, extensive FB on BM, 28–32 mm MO.	Thick bundles of CF, slight oedema, mature fibroblasts with scant cytoplasm and spindle shaped nuclei, inflammatory infiltrate mainly neutrophils and plasma cells, hick muscle fibers, flat rete ridges, varying degree of atrophy.
		Stage IV	Severe trismus, extensive FB on any site of OM, anemia, malnutrition, MO <10 mm.	Smooth, completely hyalinized CF, absence of oedema, no fibroblasts, destructive BV, inflammatory infiltrate mainly lymphocytes and plasma cells, muscle degeneration, epithelium may show mild to moderate atypia.
Jani and Dudhia (2016)	Firstly categorized OSMF patients according to “Khanna and Andrade system,” then modified this classification system by adding more clinical features retaining the histological features as such and proposed a newer staging system of OSMF.	Group I	CI Normal MO (35–45 mm) BS only on consuming spicy or hot food, blanching of FP, SP, and BM, normal tongue protrusion, no palpable FB.	HI Hyperkeratotic epithelium, intracellular oedema, basal cell hyperplasia, rete ridges present. Thin collagen, fibers marked oedema, large aggregate of plump, young fibroblasts having abundant cytoplasm, normal, dilated and congested BV, inflammatory cells mainly neutrophils and few eosinophils.
		Group II	C II MO (25–38 mm), BS on eating normal food, blanching of FP, SP, BM and LM, normal tongue protrusion, palpable FB in the FP, palate, and BM.	H II Atrophied epithelium with less prominent rete ridges, variable keratinization, JEH. Thick CF separated with oedema, moderate number of plump young fibroblasts, dilated and congested BV, inflammatory cells mainly lymphocytes, eosinophils, and occasional plasma cells.
		Group III	C III MO (20–30 mm), severe BS even in absence of stimuli, blanching of FP, SP, BM, LM and FM, tongue protrusion reduced, palpable FB in the FP, palate, BM, and LM and unilateral or bilateral lymphadenopathy.	H III Marked atrophy of epithelium with lack of rete ridges, moderately hyalinized CF, JEH. Thickened CF separated by oedema, less marked fibroblastic response, mostly adult fibrocytes present with scanty cytoplasm and spindle shaped nuclei, normal or constricted BV, inflammatory component mainly lymphocytes and plasma cells and occasional eosinophils, infiltration of muscles with CF.
		Group IV	C IV MO 15–25 mm, severe BS, blanching of FP, SP, BM, LM, and floor of the mouth, restricted tongue movement, atrophy of tongue papilla, palpable FB in the FP, palate, BM, LM and FM, hyposalivation, unilateral or bilateral lymphadenopathy, reduced movements of SP, small, shrunken, deviated or fibrous uvula.	H IV Atrophic epithelium, absence of rete ridges, completely hyalinized collagen with the, absence of oedema, absence of fibroblasts, completely obliterated or narrowed BV, inflammatory cells mainly lymphocytes and plasma cells, extensive degeneration of muscle fibers.

BM: buccal mucosa, BS: burning sensation, BV: blood vessels, CF: collagen fibers, FB: fibrous bands, FM: floor of the mouth, FP: faucial pillars, JEH: Juxta-epithelial hyalinization, LM: labial mucosa, MO: mouth opening, OM: oral mucosa, SP: soft palate

Table 6.

Classification of oral submucous fibrosis based on clinical, functional and histopathological parameters (Ref-18)

Grading/staging	Clinical	Functional	Histopathological	Treatment	Prognosis
Grade I	Involvement of <1/3rd of the oral cavity, mild blanching, BS, recurrent ulceration, and stomatitis. dryness of mouth.	MO up to 35 mm	Stage of inflammation Fine edematous collagen, congested BV, abundant neutrophils along with lymphocytes with myxomatous changes in subepithelial CT layer of epithelium.	Cessation of habit, nutritional support, antioxidants, topical steroid ointment.	Excellent.
Grade II	Involvement of 1/3rd to 2/3rd of the oral cavity, blanching, mottled and marble like appearance, palpable FB, involvement of SP and premolar area.	MO 25–35 mm, CF reduced by 33%	Stage of hyalinization Juxta-epithelial collagen hyalinization, lymphocytes, eosinophils, dilated and congested BV, less fibroblastic activity. granulation changes in muscle layer with reduced inflammatory cells in the subepithelial layer.	Habit cessation, nutritional supplement, intralesional injection of placental extracts, hyaluronidase, steroid therapy physiotherapy	Good, recurrence rate is low.
Grade III	Involvement of greater than >2/3rd of the oral cavity. Severe blanching, Broad thick palpable FB at cheeks and lips and rigid mucosa, depapillated tongue and restricted tongue movement, shrunken bud like uvula, FM involvement and lymphadenopathy	MO 15–25 mm, CF reduced by 66%	Stage of fibrosis Complete collagen hyalinization without fibroblasts and oedema, obliterated BV, plasma cells and lymphocytes, extensive fibrosis with hyalinization from subepithelial to superficial muscle layers with atrophic, degenerative changes.	Surgical treatment including band excision and reconstruction with graft, bilateral temporalis myotomy and coronoidectomy.	Fair, recurrence rate is high.
Grade IV	Changes like leukoplakia, erythroplakia ulcerating and suspicious malignant lesion.	MO < 15 mm or nil	Stage of malignant transformation Erythroplakia changes into squamous cell carcinoma.	Surgical treatment, and biopsy of suspicious lesion.	Poor, malignant transformation.

BS: burning sensation, BV: blood vessels, CF: check flexibility, CT: connective tissue, FB: fibrous bands, FM: floor of the mouth, MO: mouth opening, SP: soft palate

Table 7.

TFM classification of oral submucous fibrosis given by Arakeri et al.[28]

TRISMUS (T)

TX: Trismus cannot be assessed because of the presence of factors such as tooth impingement, TMJ disorders, infection, etc.

T0: IID > 36mm.

T1: IID 26–35 mm.

T2: IID 15–25 mm.

T3: IID < 15 mm.

TE: Edentulous (E) state because of either complete or partial loss of anterior teeth.

TE0: Anterior free space after MO >41 mm.

TE1: Anterior free space after MO 36–40 mm.

TE2: Anterior free space after MO 25–35 mm.

TE3: Anterior free space after MO < 25 mm.

FIBROSIS (F)

F0: No signs of fibrosis.

FX: Fibrosis cannot be assessed because of severe trismus.

F1: BS in the mouth and/or blanching of OM and/or acute ulceration and/or recurrent stomatitis.

F2: Mottled and marble like OM, dense, pale, depigmented fibrosed areas alternated with pink normal mucosa, widespread sheets of fibrosis involving labial and/or BM and/or oropharynx.

F3: Pale OM, firmly attached to underlying tissues, palpable vertical FB at the BM, in SP-radiating FB from the pterygomandibular raphe or the anterior FP in a scar-like appearance, atrophy of the vermilion border, patient unable to blow out cheeks and whistle.

F4: Thickened FP, shrunken-fibrous bud like small uvula, narrowed isthmus, restricted tongue movement, diffuse papillary atrophy, palpable circular FB around entire mouth, obliquity of rima oris, vermilion border atrophy.

MALIGNANT TRANSFORMATION (M)

M0: No signs of malignant transformation.

MX: Malignant transformation cannot be assessed because of severe trismus.

MQ: Lesion in question.

MP: Associated potentially malignant disorder.

M1: Histopathological evidence of dysplasia.

M1a: Low-grade.

M1b: High-grade.

M2: Histopathological evidence of malignant transformation.

STAGING:

Stage 1 (medical therapy): T0-2/E0-E2 or F1-2, M0,1a

Stage 2 (surgical therapy): T2-3/E2-E3 or F3-4, M0,1b

Stage 3 (neoplastic disease therapy): Any T, F1-4, M2

BM: buccal mucosa, BS: burning sensation, E: edentulous, FB: fibrous bands, FM: floor of the mouth, FP: faucial pillars, IID: interincisal distance, MO: mouth opening, OM: oral mucosa, SP: soft palate, TMJ: temporomandibular joint

RESULTS

In total, our search strategy revealed 250 articles. After excluding duplicates and those not meeting inclusion criteria, a total of 31 relevant articles were included in our systematic review presenting variable classifications given for OSMF. It could be appreciated that OSMF was classified in the following ways:

• Based on clinical parameters [Table 1].[10,11,12,13,14,15,16,17,18]

• Based on functional parameters [Table 2].[17,18,19,20,21,22,23]

• Based on clinical and functional parameters [Table 3].[24,25]

• Based on histopathological parameters [Table 4].[18,19,26]

• Based on both clinical and histopathological parameters [Table 5].[17,27]

• Based on clinical, functional, and histopathological parameters along with treatment plan and prognosis [Table 6].[18]

• TFM (Trismus, Fibrosis, Malignant transformation) classification [Table 7].[28]

DISCUSSION

For many years, researchers have proposed a number of grading/staging systems of OSMF based on variable parameters. Strengths and weaknesses of these classifications supersede each other leading to a confusion [Table 8]. Despite lot of research, still there is no reliable system that could be universally accepted and employed by clinicians, surgeons, and pathologists for accurate diagnosis and treatment plan.

Table 8.

Strengths and weaknesses of various classification systems of oral submucous fibrosis (possible factors)

S.No.	Classification	Strengths	Weaknesses
1.	Based on clinical parameters.	• Simple and easy to apply.	• May be time consuming. • Criteria vary for each classification given by different authors. • Grouping OSMF patients with malignant transformation in late stages may result in losing vital data with prognostic value. • Represent only the prominent lesion rather than potential changes in rest of oral cavity. • Degree of malignant transformation can’t be assessed in detail. • Fail to explain the factors leading to trismus and fibrosis. • False staging may occur because of repetition of features and inappropriate data collection.
2.	Based on functional parameters.	• Simple and easy to apply.	• It is not reliable to classify the disease only on the base of single parameter. • Trismus can be clinical feature too. • Range of MO varies from one classification to another. • Does not include other clinical features and degree of malignant transformation of OSMF.
3.	Based on clinical and functional parameters.	• Provide separate staging for both clinical and functional parameters.	• May be time consuming. • Criteria vary for each classification given by different authors. • Degree of malignant transformation can’t be assessed in detail. • Trismus can be clinical feature also. • Fail to explain the factors leading to trismus and fibrosis. • False staging may occur because of inappropriate criteria.
4.	Based on histopathological parameters.	• Helps to assess the progressive changes in the underlying tissues of OM.	• Can’t monitor the disease. • Role in treatment plan is uncertain. • Histological changes can’t always corelate with clinical symptoms.
5.	Based on both clinical and histopathological parameters.	• Helps to assess the progressive changes in the underlying tissues of OM and to determine the clinical symptoms of the disease.	• Histological changes can’t always corelate with clinical symptoms. • Reporting malignant changes in the late stage may lead to inappropriate treatment plan. • May be time consuming, as it involves the assessment of each feature individually.
6.	Based on clinical, functional, and histopathological parameters.	• Includes all the three parameters of OSMF. • Provides separate grading/staging for each component. • Helps to determine prognostic outcomes and treatment plans for the disease according to the stage.	• Complex and difficult to remember. • May be time consuming, as it involves the assessment of each feature individually.
7.	TFM classification.	• Includes all the three parameters of OSMF. • Can distinguish between trismus and fibrosis. • Helps to assess trismus resulting from other factors. •Helps to determine the prognostic outcomes and treatment plans for the disease according to the stage.	• Complex and difficult to remember. • May be time consuming, as it involves the assessment of each feature individually. • Needs careful observation and evaluation of the criteria used to classify the disease.

MO: mouth opening, OM: oral mucosa, OSMF: oral submucous fibrosis, TFM: trismus, fibrosis, malignant transformation

Our literature research revealed that OSMF has been classified based on several parameters. Classifications based on its clinical parameters seem to be simple and easy yet fail to provide the detailed aspects of the disease for the accurate grading/staging.[10,11,12,13,14,15,16,17,18] And no consistency has been established for providing a single acceptable criteria.

Many researchers classified OSMF based on only functional parameters, such as range of MO or cheek flexibility (CF),[17,18,19,20,21,22,23] but it is not reliable to grade the disease based on just a single parameter. Because OSMF presents with the wide involvement in oral cavity, it is essential to depict the other signs and symptoms also. Moreover, in every classification, the range of MO varied. Restriction of MO leading to trismus can also be because of some other etiological and contributory factors, such as any temporomandibular joint disorder, osteomyelitis, scleroderma, any neoplastic swelling, and infection, so these classification systems may lead to inappropriate staging. Moreover, in the presence of severe trismus, it may become difficult to notice other clinical symptoms completely, leading to false staging. Classifying the disease based only on CF is also not relevant criteria ignoring other important features of OSMF. Thus, functional classification also fails to be followed as an accepted system.

Classifications involving clinical and functional staging[24,25] do not emphasize on the extent of involvement of other regions of the oral cavity and the degree of malignant transformation. Moreover, it has been found that trismus can be one of the clinical features of OSMF, so the use of term “clinical” and “functional” together seems to be inappropriate. Also, range of MO given in both systems is not consistent to be followed universally.

Although diagnosis of OSMF is sufficient on the basis of its clinical features, yet histopathology is essential to evaluate the progression of associated changes in the underlying OM of these patients. Few scholars classified OSMF only on the basis of only histopathology.[18,19,26] However, histopathological grading can assess only the progress of disease, its role in monitoring and treatment plan is not certain. Among all OPMDs, the malignant transformation behavior of OSMF is somehow different and unique. Usually, any malignancy is proceeded by increased grades of epithelial dysplasia, increased vascularity and number of blood vessels, whereas OSMF progresses with enhanced fibrotic component along with reduced angiogenesis that may return to increased vasculature indicating its malignant potential, but these criteria are not always easy to follow, leading to difficulty in predicting its carcinogenic behavior.

Classifying only on the basis of thickness of collagen fibers ignoring other histological features cannot be considered as a reliable method of staging.[19]

Classifications based on clinicopathological parameters may be considered valuable to certain extent, but still there is the need to evaluate clinicopathological co-relation of the disease.[17,27] Because OSMF is a heterogeneous disease, the extent of involvement into the oral cavity may vary. Many studies have been conducted to evaluate this clinicopathological co-relation and it has been appreciated that the results are not always statically significant. Sometimes the histological changes seen in the oral tissues do not correspond with the clinical symptoms. So, the final staging given on this basis can lead to wrong approach of treatment.

Classification proposed by Passi et al.[18] included all the parameters separately, such as clinical, functional, and histological along with treatment therapy and prognosis of the disease. This system may be helpful for the clinicians for effective communication, categorization, evaluating prognosis, and guiding treatment plans. But it does not explain malignant component of OSMF in details, so sometimes leading to an inaccurate treatment approach. Also, it seems to be complicated to memorize and to evaluate the detailed aspects of each component.

TFM system by Arakeri et al.[28] considered all the main components of OSMF, that is, T, F, and M. This system indicates that the components associated with structural progression of OSMF are independent of each other and the altered tissue architecture varies from one region to another. It can assess trismus resulting from factors other than mucosal fibrosis, its incidence in edentulous mouth and when clinical assessment is not possible because of severe trismus. It uses clinical parameters which indicate the severity of disease. The malignant transformation component guides in assessing the possible malignant changes in the lesion, any dysplasia, or frank carcinoma. It also helps in consideration when the assessment of the lesions is not possible because of lack of proper visibility. Moreover, it also helps to divide the dysplastic features into low and high risk. This possible classification helps to differentiate between the need of medical, surgical and advanced therapeutic aids in the management of disease. But it is too complicated to remember and time consuming.

OUR PROPOSED CLASSIFICATION BASED ON LITERATURE RESEARCH

Based on this systematic review, we have attempted to propose a new classification system for OSMF. We included clinical, functional, and histopathological parameters and gave individual grades. Then final Five cumulative grades were given indicating the severity of the disease (Table 9). Previously, many researchers have given their classifications based on these parameters, but none has provided a cumulative grade. The main strength of our classification is the cumulative grading based on individual parameters of OSMF assessing the progression of the disease. It involves all the essential details of the features associated with this disease. The present classification seems to be simple and easy to remember allowing pathologists and clinicians to grade OSMF accurately for implementing proper treatment plans to prevent further complications.

Table 9.

Our proposed classification of oral submucous fibrosis based on literature research

Parameter	Grading
Clinical	S1: Mild stage: Mild clinical features such as BS, Vesicle formation, ulceration, Normal tongue movement, no FB. Involving 1/3rd of oral cavity. S2: Moderate stage: Clinical features such as blanching, mottled and marble like appearance, Palpable FB. Involvement of 1/3rd-2/3rd of the oral cavity, S3: Moderately advanced stage: Clinical features such as severe blanching, thick palpable FB occupying multiple sites, depapillated tongue and restricted tongue movement, shrunken bud like uvula, FM involvement and lymphadenopathy. Involvement of >2/3rd of the oral cavity, S4 A: Any of the above features along with dysplastic changes like leukoplakia, erythroplakia etc. S4 B: Changes showing evidence of OSCC.
Functional	M1: MO 35-40 mm M2: MO 25-35 mm M3: MO 15-25 mm M4A: MO 10-15 mm M4B: MO <10 mm
Histopathological	H1: Hyperkeratosis, lack of rete ridges, Fine collagen, intracellular oedema, plump young fibroblasts, congested BV, inflammatory infiltrate mainly neutrophils along with lymphocytes, myxomatous changes in subepithelial CT. H2: Atrophied epithelium with less prominent rete ridges, variable keratinization JEH, moderate number of plump young fibroblasts, dilated and congested BV, lymphocytes, eosinophils. H3: Marked atrophy of epithelium with lack of rete ridges, moderately hyalinized CF, JEH, thickened CF separated by oedema, less marked fibroblastic response, abundant of mature fibrocytes, normal or constricted BV, inflammatory infiltrate mainly lymphocytes and plasma cells and occasional eosinophils, extensive fibrosis with muscle degenerative changes. H4A: Atrophic epithelium, absence of rete ridges, completely hyalinized collagen with absence of oedema, absence of fibroblasts, completely obliterated or narrowed BV, inflammatory cells mainly lymphocytes and plasma cells, extensive degeneration of muscle fibers. Dysplastic changes into epithelium. H4 B: Evidence of dysplastic changes progressing into OSCC.
Cumulative grade: Grade 1: MILD: S1M1H1, S1M2H1 (good prognosis) Grade II: MODERATE: S1M2H2, S2M1H1, S2M2H2 (favorable prognosis) Grade III: MODERATELY ADVANCED: S2M3H3, S3M3H3 (fair prognosis) Grade IV: ADVANCED: S4AM4AH4A, S4AM4BH4A (poor prognosis) GRADE V: MALIGNANT: S4BM4BH4B, S4BM4AH4B (worst prognosis)

BS: burning sensation, BV: blood vessels, CF: collagen fibers, CT: connective tissue, FB: fibrous bands, FM: floor of the mouth, JEH: juxta-epithelial hyalinization, MO: mouth opening, OSCC: oral squamous cell carcinoma, SP: soft palate

LIMITATIONS OF CURRENT RESEARCH

The limitation of current research is the lack of accurate statistical analysis done in the various studies to interpret the drawbacks and merits of vivid classification systems given.

CONCLUSIONS

Despite the existence of several classification systems of OSMF, it is still a challenging task for clinicians, surgeons, and pathologists to accept and follow a reliable classification scheme that could help in the accurate assessment of the progression of the disease so that proper treatment plans could be followed at an early stage for preventing further complications. Though we have attempted to propose a new classification system based on this systematic review, still a robust research is needed in this aspect.

ABBREVIATIONS USED

AN: Areca nut; BM: Buccal mucosa; BS: Burning sensation; BV: Blood vessels; CF: Cheek flexibility; EP: Erythroplakia; FB: Fibrous bands; FM: Floor of the mouth; FP: Faucial pillars; IID: Interincisal distance; JEH: Juxta‑epithelial hyalinization; LM: Labial mucosa; LP: Leukoplakia; MO: Mouth opening, MMO: Maximum mouth opening; OM: Oral mucosa, OPMD: Oral potentially malignant disorder; OSMF: Oral submucous fibrosis; OSCC: Oral squamous cell carcinoma; PRMO: Percentage of reduction in mouth opening; SP: Soft palate; TFI: Three finger index; TFM: Trismus, Fibrosis, Malignant transformation;TMJ: Temporomandibular joint; WHO: World health organization.

FINANCIAL SUPPORT AND SPONSORSHIP

Nil.

CONFLICTS OF INTEREST

There are no conflicts of interest.

AUTHORS CONTRIBUTIONS

Sonia Gupta: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Validation, Writing-original draft, Writing-review & editing.

Anitha Subbappa, Shivani Singh, Pallavi Sharma: Data curation, Investigation, Methodology.

Ankita Singh, Aakash Kumar: Data curation, Investigation, Methodology, Validation.

Harman Sandhu, Karthick Thangamani Nadar: Data curation, Project administration, Supervision, Visualization.

ETHICAL POLICY AND INSTITUTIONAL REVIEW BOARD STATEMENT

Not required for the current research.

PATIENT DECLARATION OF CONSENT

Not required for the current research.

DATA AVAILABILITY STATEMENT

All data is available in the tables, no other data can be shared.