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Year : 2017  |  Volume : 13  |  Issue : 3  |  Page : 399-405

An update on studies on etiological factors, disease progression, and malignant transformation in oral submucous fibrosis

Department of Oral and Maxillofacial Pathology, Pacific Dental College and Hospital, Udaipur, Rajasthan, India

Date of Web Publication31-Aug-2017

Correspondence Address:
Samiha Bari
Department of Oral and Maxillofacial Pathology, Pacific Dental College and Hospital, Udaipur, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.179524

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 > Abstract 

Worldwide estimates of oral submucous fibrosis (OSMF) show a confinement to Indians and Southeast Asians. In India, the prevalence of OSMF has increased over the past four decades from 0.03% to 6.42%. The condition is well recognized for its malignant potential rate of 7-30%. The condition has a multifactorial etiology and may remain either stationary or become severe, leaving an individual physically challenged both physically and psychologically. Hence, the study aims at reviewing studies done on various etiological factors leading to its onset. Their analysis may serve as an adjunct in defining the broad spectrum of the causation of this potentially malignant disorder.

Keywords: Etiological factors, oral submucous fibrosis, recent update

How to cite this article:
Bari S, Metgud R, Vyas Z, Tak A. An update on studies on etiological factors, disease progression, and malignant transformation in oral submucous fibrosis. J Can Res Ther 2017;13:399-405

How to cite this URL:
Bari S, Metgud R, Vyas Z, Tak A. An update on studies on etiological factors, disease progression, and malignant transformation in oral submucous fibrosis. J Can Res Ther [serial online] 2017 [cited 2021 Jul 26];13:399-405. Available from: https://www.cancerjournal.net/text.asp?2017/13/3/399/179524

 > Introduction Top

Unlike other potentially malignant disorders, oral submucous fibrosis (OSMF) is insidious in origin and is not amenable to reverse at any stage of the disease either spontaneously or with cessation of habit. The condition may remain either stationary or become severe, leaving an individual challenged both physically and psychologically.[1]

Pathogenesis is believed to involve juxta-epithelial inflammatory reaction and fibrosis in the oral mucosa, probably due to an increased cross-linking of collagen through up-regulation of lysyl oxidase activity. Fibrosis, or the building up of collagen, results from the effects of areca nut, which increases collagen production (e.g., stimulated by arecoline, an alkaloid) and decreases collagen degradation.[2],[3] Thus, OSMF is now considered a collagen metabolic disorder.[4]

 > Epidemiology Top

An epidemiological survey done have shown an increase in number in India from 250,000 cases reported in 1980 to 2 million cases in 1993.[5] The epidemiological assessment of the prevalence of OSMF among Indian villagers, based on baseline data, recorded a prevalence of 0.2% (n: 10,071) in Gujarat, 0.4% (n: 10,287) in Kerala, 0.04% (n: 10,169) in Andhra Pradesh, and 0.07% (n: 20,388) in Bihar. The prevalence among 101,761 villagers in the state of Maharashtra (central India) was 0.03%.[2] A study of Moradabad district (Nigam et al., 2014)[6] showed a prevalence rate of 6.3% while a study of rural Jaipur population (Sharma et al., 2012)[7] showed prevalence rate of 3.39%. The variation can be due to difference in the availability of different products.

 > Etiological Factors Top

OSMF has a malignant transformation rate (to oral squamous cell carcinoma [OSCC]) of 7-30%.[8] A multifactorial model for the pathogenesis of OSMF has been postulated and is known to have either a direct effect in causing OSMF or an indirect effect by mediating the immune system which is compromised in OSMF.[9] Numerous studies have been conducted to assess the main etiological factor causing this debilitating disease.

 > Studies Done on Various Etiological Factors Top

Areca nut

India is the largest producers of areca nut, with the South Indian states of Karnataka, Kerala, and Tamil Nadu contributing to the bulk of it.[10] Epidemiological data and intervention studies suggest that areca nut is the main etiological factor for OSMF.[11] Areca nut is high in copper and plays an important role in pathogenesis of OSMF.[12] Copper content in various betel quid ingredients has been reported to range from 3 to 108 mg/g in areca nut and from 8 to 53 mg/g in pan masala.[13] The enzyme lysyl oxidase is a copper activated enzyme critical for collagen cross-linking and organization of extracellular matrix.[14]

Pillai and Burde[15] conducted a study to determine the copper level in serum and buccal mucosa of OSMF patients who are habitual chewers of areca nut-containing products such as gutkha, pan, and pan masala. No significant difference in serum copper level was observed between the OSMF patients and control subjects (P > 0.05) whereas the difference in copper level in the tissue was significant (P < 0.01), the level being 2.47-fold higher in the patients.

Sami et al.[16] conducted a study where comparative severity of OSMF among gutkha and other areca nut products chewers was carried out. 63% cases chewed gutkha and other areca nut products for <2 years suffered from grade I, 24% who chewed for 2–4 years developed grade III. The patient who were taking <2 pouch per day and keeping for <2 min mostly developed grade I whereas patients who were taking more than 10 pouches per day and keeping 5–10 min in the mouth developed grade III. About 60% who chewed gutkha and other product and spitted out after keeping few minutes developed grade I and who chewed and swallowed it after keeping in the mouth or kept longer period in buccal vestibules developed grade III OSMF.

Khan et al.[17] studied the global gene expression profile in epithelial cells (HaCaT) following treatment with areca nut water extract or transforming growth factor-beta (TGF-β). Interestingly, 64% of the differentially regulated genes by areca nut water extract matches with the TGF-β induced gene expression profile. Out of these, expression of 57% of genes was compromised in the presence of ALK5 (TβRI) inhibitor and 7% were independently induced by areca nut, highlighting the importance of TGF-β in areca nut actions.

Mathew et al.[7] assessed and compared copper content in raw areca nuts and commercial areca nut products. Raw areca nut samples of three different maturities were obtained from four plantations in Sullia, Karnataka, India, and commercial areca nut products were obtained from local shops in Chidambaram, Tamil Nadu, India. Among raw areca nut, copper content was least in the unripe areca nut (3.64 ± 0.84 mg/kg) and was highest in the exfoliated mature areca nut. Ripened areca nut showed intermediate values (7.84 ± 0.81 mg/kg). The copper level in commercial products was higher (11.39 ± 1.02 and 12.83 ± 0.63 mg/kg) than the raw areca nut. It was found that during processing of areca nut for commercial purpose, the moisture content was further reduced by drying or roasting. The nut becomes more concentrated with its mineral and chemical constituents. This increase in mineral concentration of nut on processing explains the higher copper content in the commercial areca nut products. The dry weight of nut also reduces significantly along with volumetric shrinkage as it loses the moisture content during the processing. Thus in effect, individuals using commercial products will be consuming areca nut which is rich in copper compared to those who use raw areca nut.

Arecoline a product of areca nut was found to elevate cystatin C mRNA (CST3) and protein expression in a dose-dependent manner. Cystatin C expression was significantly higher in OSMF specimens and expressed mainly by fibroblasts, endothelial cells, and inflammatory cells. Cross-links between the molecules are essential for the tensile strength of collagen fibers. These areas are resistant to attack by collagenases but can be attacked by a number of other serine and cysteine proteinases. CST3 encoding a cysteine proteinase inhibitor might contribute to the stabilization of collagen fibrils in OSMF. Treatment directed against cystatin C may serve as a novel treatment for submucous fibrosis and also in preventing its transformation into malignancy.[18]

Mohammed et al.[19] estimated the copper levels in saliva of patients with OSMF and different areca nut products and its correlation with different histological grades. The mean salivary copper level was 27.023 μg/dl in OSMF patients when compared with 8.393 μg/dl in non-OSMF individuals (P < 0.005). The mean copper content in different areca nut products was 13.313 ppm (P < 0.005). Comparison of copper content in different areca nut products with salivary copper levels of OSMF patients showed negative correlation (P < 0.853). Comparison of salivary copper levels between different histological grades of OSMF yielded a statistically significant association between grades I and III (P < 0.005) and grades II and III OSMF (P < 0.019). Comparison of copper content in areca nut products and different histological grades of OSMF yielded weak negative statistical correlation (r = −0.116).

Lee et al.[20] used arecoline, a major areca nut alkaloid, to explore whether expression of Twist could be changed dose-dependently in human primary buccal mucosal fibroblasts (BMFs). Collagen gel contraction and migration capability in arecoline-stimulated BMFs and primary OSMF-derived fibroblasts (OSMFs) with twist knockdown was presented. They observed that the treatment of arecoline dose-dependently increased twist expression transcript and protein levels in BMFs. The myofibroblast activity including collagen gel contraction and migration capability also induced by arecoline, while knockdown of twist reversed these phenomena. Importantly, inhibition of twist led to the suppression collagen contraction and wound healing capability of primary cultivated OSMFs. Clinically, twist transcript and protein expression were higher in areca quid chewing-associated OSMF tissues than in normal oral mucosa tissues. Thus, the evidence suggests that up-regulation of twist might be involved in the pathogenesis of areca quid-associated OSMF through dysregulation of myofibroblast activity.

Singh et al.[21] estimated tissue copper level in OSMF patients with habit of areca nut chewing and correlated any change in tissue copper level with histopathological grading of OSMF. A highly significant difference in mean tissue copper level (P < 0.001) in patients with OSMF and controls, with patients exhibiting higher tissue copper level (6.43 ± 1.11) in contrast to control who presented low tissue copper level (4.35 ± 0.91), also a highly significant correlation (P < 0.001) was seen between increase in tissue copper level and histopathological staging of OSMF. The present study confirms the hypothesis that copper level is increased in areca nut chewers presenting OSMF. Moreover, copper level increased with increased in histopathological grade of OSMF.

Nutritional deficiencies

Nutritional deficiency, primarily of iron and vitamins is implicated in the etiology of OSMF. Hemoglobin levels as well as serum iron levels are considered as biochemical indicators for nutritional assessment.

Raina et al.[22] conducted a study to estimate the serum beta-carotene levels in patients of OSMF. Serum beta-carotene levels were below the normal range for all grades of OSMF but were lower in grade II and lowest in grade III cases.

A study was carried out by Ganapathy et al.[23] to comprehend the association between OSMF and iron deficiency anemia. Results showed that the mean values of hemoglobin and serum iron levels of control group were 14.23 ± 0.96 mg/dl and 129.90 ± 4.07 mcg/dl, whereas that of OSMF group were 12.96 ± 1.07 mg/dl and 51.56 ± 4.95 mcg/dl respectively. On comparison of OSMF group with the healthy group, OSMF group showed significantly lower levels of hemoglobin and serum iron with P < 0.001.

A study was conducted by Rupak et al.[24] to comprehend the association between OSMF and iron deficiency anemia by estimating the levels of hemoglobin and serum iron in patients diagnosed with OSMF and comparing the values with that of healthy subjects. The results showed that OSMF group showed significantly lower levels of hemoglobin and serum iron as compared to the healthy groups.

Karthik et al.[25] conducted a study to estimate hemoglobin and serum iron levels among patients with OSMF and to compare the values with healthy subjects. Results showed lower levels of hemoglobin and serum iron when compared with healthy individuals.

Guruprasad et al.[26] assessed the association between OSMF, Vitamin C and iron. The results showed a significant lower level of Vitamin C and iron in patients of OSMF than healthy individuals.

Yallamraju et al.[27] conducted a study where the mid upper arm circumference of OSMF patients were measured, and an inverse relationship was found between the mid upper arm circumference and the clinical staging.

Infectious agents

Candida species cause common oral fungal infections in human beings. The presence of Candida in the mouth together with epithelial changes may predispose individuals to candidal infection. Candida albicans is the primary cause of oral candidiasis. These opportunistic fungal pathogens may colonize, invade and induce lesions in any part of the oral cavity in both immunocompetent and immunocompromised individuals. C. albicans is the predominant species isolated in premalignancy and carcinoma.

Several predisposing factors may be present in patients with OSMF, but epithelial atrophy is considered one of the key features of OSMF. Decreased mouth opening may predispose an individual to candidal growth, and this Candida can further predispose the mucosa for malignant transformation through the process of nitrosation. Thus, a study was conducted by Anila et al.[28] to determine the incidence, intensity and species of Candida present in the oral cavity of OSMF patients and healthy controls. A higher incidence and intensity of Candida was observed in OSMF patients when compared to healthy individuals, but these findings were within normal limits (3–47%). Candida may not be an etiologic factor in malignant transformation in OSMF patients.

Genetic susceptibility

OSMF has been reported in families whose members have a habit of chewing betel quid or areca nut. However, only a small fraction of those using betel quid develops OSMF thereby showing a clear genetic susceptibility. A study was conducted by Ceena et al.[29] to assess the occurrence of OSMF in individuals without chewing habits and the ones who developed the disease within 1 year of chewing gutkha and betel quid. The results showed that 2 out of 253 patients without any history of gutkha chewing developed the disease, 3% developed the disease within <6 months of chewing gutkha. Thus apart from other etiological factors, genetic susceptibility predisposes an individual to develop OSMF.

Other local factors

The pathogenesis of OSMF was first linked with the continuous and prolonged action of mild irritants on the oral mucosa.[30] The use of tobacco along with areca nut in betel quid may also be considered as one of the causative factors. Polycyclic aromatic hydrocarbons are the main precarcinogens in tobacco smoke. They are activated to ultimate carcinogens in cells by microsomal complex enzymes commonly referred to as aryl hydrocarbon hydroxylases.

Copper in drinking water

Copper is widely used in household plumbing materials. Copper leaches into water through corrosion. Arakeri et al.[31] conducted a study to evaluate that OSMF was significantly associated with a raised concentration of copper in drinking water. The study was carried out in a heterogeneous population in Hyderabad, Karnataka, India, a region with a high incidence of the condition. They evaluated three groups, each of 100 patients: Those with OSMF who chewed gutkha, those who chewed gutkha but did not have OSMF, and healthy controls who did not chew gutkha. The difference between the groups in the mean concentration of copper in water measured by atomic absorption spectrometry was significant (P < 0.001). There were also significant differences between the groups in mean concentrations of serum copper, salivary copper, and ceruloplasmin (P < 0.001). The results confirm that copper in drinking water contributes to the pathogenesis of OSMF, but ingestion of copper is unlikely to be the sole cause.

 > Factors to Assess Disease Progression Top

Genetic damage

Udupa et al.[32] undertook a pilot study to assess the deoxyribonucleic acid (DNA) damage in OSMF and healthy groups using comet assay. Results indicated an increase in the tail length in buccal epithelial cells of OSMF group when compared with the healthy group. Furthermore, there was a significant increase in the DNA damage with duration of habits. It can be concluded that an increase in the tail length formation in OSMF groups when compared to healthy groups indicates DNA damage in the oral epithelial cells.

Immunological factors

Rajendran et al.[33] undertook a study to assess the immune status of OSMF patients in comparison with that of patients suffering from oral leukoplakia and oral cancer (OC). Results showed that there was no change in any of the immunoglobulin (Ig) fractions in oral leukoplakia whereas a significant rise in IgA, IgD and IgE levels was observed in OSMF and OC. The rise of these Ig values in OC was much higher than that in OSMF. IgG and IgM showed no alterations either in the premalignant conditions (leukoplakia and OSMF) or in the malignant condition. The changes in serum Ig levels may start much before the actual clinical symptoms appear and may be used as parameters to assess humoral immunity.

Pujari and Vidya[34] conducted a study to find possible correlation between mast cells (MCs) in OSMF. The density of MC increased with disease progression. The densities of MC were significantly higher in OSMF than in normal buccal mucosa. The results suggest that MC has a definite role in initiation and progression of OSMF.

Antioxidant enzyme levels

Gurudath et al.[35] conducted a study to estimate and compare erythrocyte superoxide dismutase (SOD) and glutathione peroxidase levels in OSMF, oral leukoplakia and OC patients and age/sex matched healthy subjects. Oral leukoplakia group showed lower levels in comparison with OSMF (P > 0.05). OC group had the lowest levels amongst the study groups. Thus, it can be concluded that an imbalance in antioxidant enzyme status may be considered as one of the factors responsible for the pathogenesis of cancer and may serve as a potential biomarker and therapeutic target to reduce the malignant transformation in oral premalignant lesions/conditions.

The growth factors such as basic fibroblastic growth factor (bFGF), TGF-β, platelet derived growth factor and hypoxia inducible factor (HIF) play important roles in maintaining the vascularity of underlying connective tissue of OSMF. There is a conventionally believed concept that the epithelial atrophy in OSMF is due to lack of perfusion, caused by decreased vascularity of subjacent connective tissue stroma. Pandiar and Shameena[36] evaluated immunoreactivity of CD34 and bFGF in different histological grades of OSMF. Mean vascular density was found to decrease significantly as the diseases advanced. Furthermore, vascularity increased significantly in cases of OSMF turning toward malignancy. This study supports the concept of epithelial atrophy aftermath of lack of perfusion. There is reduced vascularity as the disease advances, and this denies the systemic absorption of carcinogens, which affects the already compromised epithelium. Consequently, liberation of angiogenic factors occurs because of malignant transformation, which explains the neoangiogenesis and increased vascularity in OSMF turning toward malignancy.

Avinash Tejasvi et al.[37] estimated the level of lipid peroxidation product (malondialdehyde [MDA]) and the activities of antioxidative enzymes SOD and correlation of these parameters in OSMF. The estimation of lipid peroxidation such as MDA showed increased levels in the OSMF group compared to the control group and antioxidant enzyme levels such as SOD showed decreased levels in the OSMF group compared to the control group.

Kadiyala[38] aimed to evaluate the salivary lactate dehydrogenase hydrolytic enzyme (LDH) levels in OC, OSMF among the control individuals and to correlate the LDH levels in these selected cases using the relatively noninvasive saliva as the diagnostic tool. The study showed significant difference in salivary LDH level between healthy controls and OSMF subjects and also healthy controls and OC subjects. LDH levels were increased in OSMF cases than the healthy controls. So estimation of salivary LDH level could be a reliable marker to diagnose OSMF (premalignant condition) and OC. It is a good noninvasive and cost effective investigation. So, this is helpful to diagnose the disease in early stages itself.

Sivaramakrishnan et al.[39] estimated the LDH levels in saliva and serum of subjects with OSMF and compared them with healthy controls to correlate the relationship between pathogenesis of OSMF and the LDH enzyme. Salivary LDH was greater in OSMF than normal individuals and this was statistically significant. On comparing the serum and salivary LDH in OSMF patients with the clinical staging of OSMF, the results were not statistically significant. Similarly, no statistically significant relationship was found on comparing the serum and salivary LDH in OSMF subjects with duration of habit. This study provides additional rationale for the role of salivary LDH in the early diagnosis and prognosis of OSMF.

 > Markers for Assessing the Malignant Transformation Potential Top

Few immunohistochemical studies have been carried out to detect markers involved in OSMF. A study was done by Ranganathan et al.[40] to characterize the cytokeratin (CK) profile in OSMF. About 12% cases showed CK18 positivity, 2% CK14, 10% CK8, 16% CK5, 78% CK4, and 32% CK1 expression. These findings suggest that in the epithelium in OSMF alterations of CKs occur, similar to that seen in precancerous lesions and OC. These alterations may have a role in carcinogenesis and have the potential to be used as surrogate markers of malignant transformation.

Tilakaratne et al.[41] investigated the relationship between HIF-1α and epithelial dysplasia. All 17 samples exhibiting evidence of epithelial dysplasia expressed HIF-1α with varying staining densities. Kale et al.[42] correlated expression of TGF-β with loss of adipose tissue in OSMF. An increased expression of TGF-β positivity was seen in early OSMF then in advanced OSMF. This suggested TGF-β to be the molecule participating in lipidodystrophy and inhibiting adipogenesis in OSMF.

Shrestha and Carnelio[43] evaluated the expression and distribution of matrix metalloproteinases-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in different grades of OSMF. All moderately advanced cases and 64.2% for MMP-2 and 78.5% for TIMP-2 of early stage cases showed positivity. Between two stages of OSMF, statistically significant differences were noted in expression of TIMP-2 in lamina propria, deep connective tissue and suprabasal layers (P < 0.05) and basal and suprabasal layers for MMP-2 (P < 0.05). The simultaneous increase in expression of MMP-2 and TIMP-2 with advancing stages of OSMF can provide a basis for considering the proteases as important mediators in the pathogenesis and progression of OSMF which could aid in identifying the aggressiveness of the condition and elucidate its role in its malignant transformation.

Kamath et al.[44] conducted a study to identify and correlate the expressions of TGF-β1 immunohistochemically on paraffin sections of various stages of OSMF. Cells of spinous layer of the epithelium showed more intense staining in all grades of OSMF, grade II showed the highest percentage of expression, same as that of keloid (17%) but less than that of normal mucosa (12%). Positive staining was seen around blood vessels, muscles, fibers in the submucosa and perimuscle fibers. Highest expression was in the muscle in grade III (80%) compared with normal oral mucosa (37%). These results suggest that the pathogenesis of OSMF and scar/keloid could be linked through the TGF-β1 pathway. Interventions directed at the TGF-β pathway may hold the key in the future management of this oral potentially malignant condition.

Daud Mirza and Nasreen Amanat (2014)[45] conducted a study to investigate the role of αγβ6 integrin in the pathogenesis of OSMF. They carried out a TGF-β1 bioassay using a keratinocyte cell line genetically modified to express high levels of αγβ6 (VB6) and found that inhibition of αγβ6 significantly reduced TGF-β1 activation (P < 0.0001). Co-culture of HFFF2 fibroblasts with VB6 cells induced myofibroblast transdifferentiation, producing a marked increase in smooth muscle actin (SMA) expression. This was inhibited using anti-αγβ6 antibodies, confirming that myofibroblast generation was αγβ6-dependent. In conclusion, these data show that αγβ6-dependent TGF-β1 activation promotes myofibroblast transdifferentiation, and may be responsible, in part, for the chronic fibrosis seen in OSMF.

Rao et al.[46] conducted a study to evaluate the presence of myofibroblasts in cases of OSMF, which consisted of very early, early and moderately advanced OSMF, OSMF with dysplasia and OSCC, by detecting α-SMA, which is a specific marker for myofibroblasts. The presence of myofibroblasts was significantly higher in OSCCs as compared to that in OSMF with dysplasia and OSMF. A statistical significance was also noted between the staining index and age of the individuals and the staining index and duration of the habit. Myofibroblasts play a role in fibrosis, as was seen in OSMF. Activated myofibroblasts secrete proteolytic enzymes and cause matrix degradation, which is instrumental in cancer cell invasion and metastasis. Further studies, in which the myofibroblasts are targetted, may help in providing therapeutic regimens in fibrosis, dysplasia and cancer.

Narayanan and Narasimhan[47] conducted a study aimed at elucidating the distribution of Langerhan cells in varying grades of OSMF. Langerhan cell population in the OSMF was significantly higher when compared to the normal epithelium (P < 0.001). Within the grades, the advanced stage had more Langerhan cells than the other stages. The increase in Langerhan cells might indicate the role of antigenic exposure in turn leading to cell mediated immunity in OSMF. Thus, the fibrosis in OSMF might have a direct link to Langerhan cells.

 > Conclusion Top

These studies are indicators of disease progress or pathways in the pathogenesis. They are parts of the puzzle that the disorder reflects. Their analysis may serve as an adjunct in defining the broad spectrum of the causation of this potentially malignant condition.

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Conflicts of interest

There are no conflicts of interest.

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