Journal of Cancer Research and Therapeutics

: 2019  |  Volume : 15  |  Issue : 3  |  Page : 463--469

Oral submucous fibrosis: An enigmatic morpho-insight

Alka Harish Hande1, Minal S Chaudhary1, Madhuri N Gawande1, Amol R Gadbail1, Prajakta R Zade1, Shree Bajaj1, Swati K Patil1, Satyajit Tekade2,  
1 Department of Oral Pathology and Microbiology, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences (DU), Wardha, Maharashtra, India
2 Department of Oral Pathology and Microbiology, Modern Dental College, Indore, Madhya Pradesh, India

Correspondence Address:
Dr. Alka Harish Hande
Department of Oral Pathology and Microbiology, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences (DU), Sawangi (Meghe), Wardha - 442 001, Maharashtra


Oral submucous fibrosis (OSMF) is a chronic progressive, scarring disease affecting oral, oropharyngeal, and sometimes the esophageal mucosa. It is characterized by the progressive fibrosis of the submucosal tissue. The pathogenesis of OSMF has been directly related to the habit of chewing areca nut and its commercial preparation, which is widespread in Indian subcontinent and Southeast Asia. The areca nut has been classified as a “group one human carcinogen.” Oral squamous cell carcinoma in the background of OSMF is one of the most common malignancies in South and Southeast Asian countries. Malignant transformation has been reported in 7%–12% cases of OSMF. Histopathological spectrum of OSMF includes the apparent alterations observed in the epithelium and connective tissue. Epithelial atrophy and sometimes epithelial hyperplasia with or without dysplasia are the peculiar alterations seen in the epithelium. In the connective tissue, there is extracellular matrix remodeling which results in excessive collagenization. Further cross-linking of collagen leads to hyalinization which makes the collagen resistant to proteolysis. Owing to fibrosis in the connective tissue, there is narrowing of blood vessels which further results in compromised blood supply to the local tissue milieu, that is, hypoxia. This tissue hypoxia elicits angiogenesis which may result in the malignant transformation of OSMF. Perpetual irritation of areca nut and its constituents to the oral mucosa leads to upregulation of pro-inflammatory cytokines and further juxtaepithelial inflammation. Thus, these coordinated reactions in epithelium and connective tissue leads the OSMF toward malignant transformation.

How to cite this article:
Hande AH, Chaudhary MS, Gawande MN, Gadbail AR, Zade PR, Bajaj S, Patil SK, Tekade S. Oral submucous fibrosis: An enigmatic morpho-insight.J Can Res Ther 2019;15:463-469

How to cite this URL:
Hande AH, Chaudhary MS, Gawande MN, Gadbail AR, Zade PR, Bajaj S, Patil SK, Tekade S. Oral submucous fibrosis: An enigmatic morpho-insight. J Can Res Ther [serial online] 2019 [cited 2019 Jun 17 ];15:463-469
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In the Indian subcontinent and Southeast Asia, habit of chewing areca nut and its commercial preparation is widespread. In India, the areca nut is used in various combinations; pan masala or kharra (powdered areca nut with tobacco and flavoring agents), betel quid (areca nut, slaked lime, and betel leaf) with or without tobacco, and raw areca nut (flakes or granules).[1] The chewing of these areca nut preparations has been recognized as one of the most important risk factors leading to a ubiquitous oral potentially malignant disorder (OPMD), oral submucous fibrosis (OSMF). OSMF is defined as a chronic progressive, scarring disease affecting oral, oropharyngeal, and sometimes the esophageal mucosa.[2] It is characterized by the progressive fibrosis of the submucosal tissue which leads to stiffness of the oral mucous membrane and restricted mouth opening.[3] The role of the constituents of areca nut in the pathogenesis of OSMF has been studied in detail over the last two decades. Most of the alterations in molecules and various pathways which lead to accumulation of collagen are mediated through it.[4] It is obvious that fibrosis of the submucosal tissues accounts for most of the manifestations of OSMF. The characteristic histopathological features of OSMF include epithelial atrophy with loss of rete ridges, increased deposition of collagen as a result of a collagen metabolic disorder caused by exposure to the areca nut alkaloids, juxtaepithelial chronic inflammatory cell infiltrate, reduced vascularity, and hyalinization of the submucosal tissue.[5]

 Malignant Transformation of Oral Submucous Fibrosis

In general, the malignant transformation of potentially malignant disorders begins with single-cell atypia subject to genetic mutation and/or various carcinogenic factors such as tobacco, betel nut, betel quid, virus, and alcohol. The areca nut being the chief causative factor for OSMF, has been classified as a “group one human carcinogen” as per the second International Agency for Research on Cancer monograph on betel quid.[6] The malignant potential of OSMF was first described by Paymaster in 1956 on the observation that one-third of the patients of oral squamous cell carcinoma (OSCC) had associated with OSMF.[7] Epithelial dysplasia has been displayed in 7%–43% cases of OSMF as reported in various studies. However, malignant transformation has been reported in 7%–12% cases of OSMF.[1]

Histopathological spectrum of malignant transformation

The malignant transformation of OSMF can be postulated on the basis of the following factors: (1) The apparent alterations observed in the epithelium are epithelial atrophy and sometimes epithelial hyperplasia with or without dysplasia. In the connective tissue, there is excessive collagenization, which further leads to hyalinization, angiogenesis, and inflammatory infiltration which may affect the malignant transformation and its further progression. (2) The OSMF is considered as collagen metabolic disorder, characterized by excessive deposition of collagen and reduced collagen degradation. Although malignancy arises in the epithelium (OSCC) and the term “malignant transformation of OSMF” infers a causal connotation between the incidence of OSCC and OSMF. (3) Discernible alterations in the epithelium and connective tissue seem to work in synchronized manner which can be appropriately regarded as epithelial–mesenchymal transitions.[1]

 Epithelial Spectrum

Epithelial atrophy

The epithelium in OSMF is thin and atrophic as denoted in the definition. In the literature, various reasons are proposed for epithelial atrophy in OSMF.

Loss of physical barrier

The salivary mucous gel (SMG) is a hydrated and thick viscous layer of salivary mucins. It acts as a physical barrier and protects the superficial cells of oral epithelium from normal physiologic frictions of the oral cavity. Apart from lubrication, it also prevents the early exfoliation of the superficial cells and thus helps to maintain the thickness and integrity of oral epithelium. In OSMF, affected minor salivary glands prevent the formation of SMG. It consequently leads to less protection and lubrication for superficial cells of the oral epithelium. This causes rapid exfoliation of superficial cells even by normal physiologic friction leading to atrophy of oral epithelium. This could explain the rationale for the presence of atrophic epithelium even though there is proliferative activity and basal cell hyperplasia.

This atrophic epithelium is more susceptible to carcinogenic attack by the use of areca nut. Hence, OSMF is considered as OPMD under the category of “morphologically altered tissue, in which external factor makes it vulnerable for malignant transformation.”[8]

Rapid exfoliation and better grade of differentiation of oral squamous cell carcinoma

It is observed that the superficial cell layer in OSMF is always well keratinized (well differentiated). This suggests that these cells are genetically programmed for high turnover rate and faster differentiation or maturation to form keratin. This genetic readaptation as a response to irritation by areca nut may be a necessary requisite to fulfill the functional requirement of protecting the underlying tissue. This explains why the OSCC arising from OSMF tend to be better differentiated/or better grade, as the altered epithelial cells retain their genetic memory of faster differentiation and maturation.[8]

Ischemic atrophy

The epithelial atrophy in OSMF is assumed to be the result of the connective tissue changes according to one school of thought. In OSMF, there is progressive fibrosis in the connective tissue which may lead to reduced degree of vascularity resulting in tissue ischemia. Hence, the “atrophy” of the epithelium in OSMF has been described as “ischemic atrophy.”[5] Apart from tissue ischemia, the cytotoxic and genotoxic effect of inducible nitric oxide synthase (iNOS) released due to areca nut alkaloids is likely to cause atrophy of epithelium. This is evidenced by reduced proliferation index of the oral epithelium in OSMF. This has been termed, epithelial hypoproliferation, rather than epithelial atrophy by Rajendran and Varkey. This leads to further reduction in thickness of surface epithelium in clinically advanced cases of OSMF.[9]

In contrast to this assumption, Desai et al.[5] suggested that the epithelial atrophy in OSMF is not due to the result of poorly vascularized stroma, that is, ischemia. However, there is neoangiogenesis which is assumed to be an adaptive response to compensate for the transitory ischemia. This assumption was proved by the demonstration of various endogenous angiogenic promoters in OSMF, such as iNOS,[9] basic fibroblast growth factor (b-FGF),[10] transforming growth factor-b (TGF-b),[11] platelet-derived growth factor (PDGF),[12] and hypoxia inducible factor-1 α (HIF-1 α).[13] The presence of vascularity in OSMF may play an important role in tumor proliferation, once the malignant transformation takes place.[5] There is no affirmative correlation of vascularity with epithelial thickness of OSMF as observed by Desai et al.[5] This discredits the conventional notion of ischemic atrophy.

Epithelial hyperplasia

In contrast to conventionally described thin and atrophic epithelium in OSMF, newer observations suggest that the epithelial thickness varies widely across different stages of OSMF. The epithelium may paradoxically show hyperkeratosis and hyperplasia, with or without dysplasia.[1] Tilakaratne et al. suggested that this epithelial hyperplasia could be an alternative adaptive response to local irritants to provide a greater degree of protection to the underlying tissues.[7] However, contrary to this, Debnath et al. observed that in each grade of OSMF, there is either hyperplastic or atrophic epithelial changes but becomes atrophic in advanced stages [14] [Figure 1].{Figure 1}

 Connective Tissue Spectrum

The main structural constituent of the connective tissue is collagen and its composition within each tissue needs to be maintained for proper tissue integrity.[11] It is commonly accepted that the pathological alteration in OSMF initiates in the connective tissue, more specifically in the lamina propria. Further, it affects the epithelium secondarily.[15] The characteristic histopathological changes in connective tissue of OSMF include fibroelastic modifications in the lamina propria and juxtaepithelial inflammatory response. Further with progression of the disease hyalinization of the submucosa and deeper tissue including muscle, salivary glands may also be affected by fibrosis;[7] juxtaepithelial inflammatory reaction may be due to response to local irritation by areca nut through physical contact with mucosa and its chemicals such as arecoline and tannins. Apart from this, varying degree of vascularity is another characteristic feature of OSMF.

Extracellular matrix remodeling

In OSMF, there is excessive collagen deposition in response to areca nut alkaloid arecoline. Furthermore, there is disequilibrium in the extracellular matrix (ECM) remodeling process which gradually increases with progression of disease. Various mechanisms have been postulated in the literature for this ECM remodeling.

Role of keratinocytes

By virtue of constant contact with oral mucosa, arecoline has local effect on the oral mucosal keratinocytes. This further triggers the excessive formation of collagen by fibroblasts through upregulation of tissue inhibitors of matrix metalloproteinase (TIMMPs) and downregulation of matrix metalloproteinase (MMPs).[16],[17],[18] This effect is enhanced when fibroblasts are cocultured with keratinocytes.[19] Thus, this triad of interaction involving arecoline, keratinocytes, and fibroblasts is responsible for improper regulation of proteolytic equilibrium among collagen deposition and its degradation, resulting in fibrosis in OSMF. This interaction is also important in malignant transformation of OSMF.

Role of connective tissue growth factor

Association of connective tissue growth factor (CTGF) with onset and progression of fibrosis is well established in many human tissues. It is suggested that reactive oxygen species elicited by arecoline activates the nuclear factor kappa B, Jun N-terminal kinase, P38 mitogen-activated protein kinase pathways, and consequent CTGF expression. Thus, fibroblastic proliferation and increased collagen formation in OSMF may be related with CTGF overexpression as evidenced by Deng et al.[20]

Role of buccal mucosa fibroblasts

Fibroblasts contraction is an important event for wound healing. However, continuous fibroblast contraction may lead to fibrotic contracture as noted in lung fibrosis, scleroderma, etc. Chang et al. found that areca nut extract stimulated buccal mucosa fibroblast-populated collagen gel contraction. Thus, they concluded that fibrosis in OSMF may be due to persistent contraction of buccal mucosal fibroblasts which is induced by arecoline in areca nut.[21]

Role of transglutaminase-2

Transglutaminase-2 (TGM-2) has been implicated in many fibrotic diseases. It is responsible for the cross-linking of collagens and further stabilization of ECM. In OSMF, overexpression of TGM-2 has been regulated by arecoline.[22]

Role of enzyme collagenase

Enzyme collagenase is responsible for degradation of collagen. This maintains the equilibrium between deposition and degradation of collagen in lamina propria. On comparison of collagenase activity in OSMF with normal oral mucosa, endogenous collagenase was found to be reduced. This explains the disequilibrium in collagen metabolism of OSMF leading to fibrosis.[23]

Role of procollagen gene

Activation of procollagen gene is major event in collagen production. The processing and/secretion of it is modulated by a collagen-specific molecular chaperone, heat shock protein 47 (HSP47). When fibroblasts were treated with arecoline, the mRNA expression of HSP47 was found to be elevated, through methyl ethyl ketone, PI3, and cyclo-oxygenase-2 signal transduction pathways. Significantly upregulated expression of HSP47 was observed in OSMF.[24]


Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. The OPMD represent altered cell populations which show morphological and functional adaptations which have attained one or more steps in the carcinogenic process. One of the earliest and perhaps most significant properties expressed by preneoplastic cell populations is their ability to elicit a neovascular response, that is, angiogenesis.[25] Thus, it would appear that expression of angiogenic activity may be predictive of malignant potential that is acquired early in the carcinogenic process.

In OSMF, it is traditionally believed that owing to fibrosis in the connective tissue, there is narrowing of blood vessels which further results in compromised blood supply to the local tissue milieu. This tissue hypoxia elicits the activation of transcription factor HIF-1 α. In OSMF, HIF-1 α has been found to be upregulated at both protein and mRNA levels. Its expression shows statistically significant correlation with degree of epithelial dysplasia. Thus, hypoxia-induced angiogenesis plays a major role in malignant transformation of OSMF as proven by expression of HIF-1α.[13]

The correlation of epithelial atrophy and angiogenesis in OSMF has been widely elucidated in the literature. The atrophic epithelium is more susceptible to the effects of oral carcinogens and further its malignant transformation.[9]

However, with the different grades of OSMF, the degree of vascularity varies as evidenced in the literature [Table 1]. Vascularity is shown to be increased in the early stage of OSMF, whereas decreased in advanced stage as evidenced by morphometric image analysis of blood vessels.[14],[26],[27],[28] The increased vascularity in early stage of OSMF may be the result of chronic inflammation due to constant irritation by areca nut constituents and hypoxia-induced angiogenesis in the connective tissue as an adaptive response due to increased fibrosis.[14],[26] As the fibrosis progresses, the mediators of angiogenesis seem to diminish which is manifested as decreased vascularity. This is evidenced by decrease in microvessel density, a measure of vascularity, in advanced stage of OSMF.[26],[29] An increase in vascularity is observed from normal to cases of OSMF transformed into malignancy, suggesting that the angiogenesis is significant issue in malignant transformation and progression.[26],[29]{Table 1}

These interpretations support the evidence of increased angiogenesis with progression of disease to malignancy. However, Rajendran et al. and Garg and Mehrotra suggested that the established conventional correlation of decrease in degree of vascularity in advanced stages of OSMF becomes invalid with observation of nonconsistent increase or decrease in vascularity with various grades of OSMF.[30],[31] Tilakaratne et al. have hypothesized that enhanced fibrosis and reduced vascularity of the submucosa, in the presence of an altered cytokine activity, makes a distinctive milieu for carcinogens from both tobacco and areca nut which act on the epithelium. They presume that reduced vascularity may possibly refute accumulation of carcinogens over an extended period in the epithelium before it disperses into deeper tissue.[32]

Apart from vascularity and degree of fibrosis, permeability of epithelium may be one of the factors in malignant transformation of OSMF. The carcinogens such as tobacco and areca nut act over the epithelium by intimate physical contact over a period of time. They act as a dehydrating agent which shrinks the cells and allow percolation of carcinogens by increasing the permeability.[1]


The process of cross-linking of collagen gives tensile strength and mechanical properties to the fibers which makes them resistant to proteolysis.[11]

Various reasons for hyalinization has been postulated in the literature.

Role of cross-linking

Arecoline and tannin, the major constituents of areca nut, reduce degradation of collagen and simultaneously enhances its production by inhibiting collagenases. This remodeling of ECM shows enhancement of perlecan, tenascin, fibronectin, and collagen Type III in early stages of OSMF, whereas with the progression of disease in advanced stages, all the ECM molecules shows degradation with complete replacement of Type I collagen.[33] Thus, these molecular changes are responsible for cross-linking of collagens and further establishment of ECM.

Role of copper

In addition to arecoline, areca nut contains other active components, such as alkaloids, polyphenols, and trace elements such as sodium, magnesium, copper, and bromine. The higher copper content of areca nut and its role in pathophysiology of OSMF is a matter of research. The enzyme lysyl oxidase (LOX) is a copper-activated enzyme mainly related to final processing of collagen fibers into a stabilized covalently cross-linked mature fibrillar form that is resistant to proteolysis.[12] There is constant contact of areca nut and its constituents with oral mucosa. Due to chewing of areca nut, copper level significantly increases in oral fluids and is further absorbs by mucosal cells, thus leading to increase fibrosis in OSMF.[34] Concentration of salivary copper level shows gradual increase from early to advanced cases of OSMF.[35] Not only in saliva but also in serum, copper levels are reported to increase with increase severity of OSMF. However, the effect of copper appears to be local in context to OSMF, as there is no clinical evidence of fibrosis involving any other organ. Thus, these molecular changes during the progression of fibrosis as measured by degree of cross-linking/hyalinization increases the risk of epithelial dysplasia in OSMF.[36]

Juxtaepithelial inflammation

Inflammatory reaction is the biological response and a protective mechanism of body tissues to any noxious stimuli. There is perpetual irritation to oral tissues due to friction caused by constituents of areca nut and their metabolites. Moreover, continuous abrasion of coarse fibers of areca nut causes microtrauma to oral mucosa which enables the alkaloids and flavonoids diffuse into subepithelial connective tissue. Eventually, the tissue response leads to juxtaepthelial inflammatory cell infiltration, which becomes chronic owing to constant irritation. This can be considered as the critical event in the pathogenesis of OSMF. The enhanced expression of pro-inflammatory cytokines mainly, interleukin 1 and 6, tumor necrosing factor, and decreased antifibrotic interferon was observed in OSMF tissue. Apart from this, the upregulation of fibrogenic cytokines TGF-β, PDGF, and b-FGF in OSMF tissue as compared to normal has been reported.[37] TGF-β is considered to be a significant regulator of ECM assembly and its remodeling. It has been found to be strongly promote the expression of LOX both at mRNA and protein level in various cell lines.[38],[39] This could be due to elevation of bone morphogenic protein 1 by TGF-β at the transcriptional and translational levels in fibrogenic cell cultures.[40] There is increased expression of HIF-1 α in fibroblasts and epithelial cells of renal and lung tissue resultant to hypoxia. Same can be postulated for the OSMF connective tissue. Further, upregulation of TGF-β through HIF-1α has also been demonstrated.[41],[42] These observations support the hypothesis that hypoxia plays a key role in progression of fibrosis in OSMF once the disease process is initiated by arecoline in betel quid [13] [Figure 2].{Figure 2}


OSMF, a ubiquitous OPMD, is considered to be a collagen metabolic disorder. There are discernible alterations in the connective tissue secondary to chewing of areca nut which further affects the surface epithelium. The carcinogenicity of areca nut has been proven by association of OSMF with OSCC. Thus, early detection of alterations in connective tissue and epithelium may prevent its malignant transformation [Figure 3].{Figure 3}

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