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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 3  |  Page : 597-603

Oral submucous fibrosis: A clinico-histopathological correlational study


1 Department of Oral Medicine and Radiology, Rural Dental College, Pravara Institute of Medical Sciences, Ahmednagar, Maharashtra, India
2 Department of Conservative Dentistry and Endodontics, Rural Dental College, Pravara Institute of Medical Sciences, Ahmednagar, Maharashtra, India
3 Department of Oral Medicine and Radiology, Shri Ramachandra Bhanj Dental College and Hospital, Cuttack, Odisha, India

Date of Web Publication12-Jun-2018

Correspondence Address:
Dr. Sudharani Basawaraj Biradar
Department of Oral Medicine and Radiology, Rural Dental College, Pravara Institute of Medical Sciences, Loni, Ahmednagar - 413 736, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.176177

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 > Abstract 


Aim of the Study: The aim of this study was to correlate the clinical staging (clinical severity) with the histopathological staging (histopathological changes) of oral submucous fibrosis (OSF) patients, which would further assist the clinicians to formulate a definite treatment plan.
Materials and Methods: The study group consisted of 50 subjects who were clinically and histologically diagnosed as OSF. Detailed information was gathered in a pretested proforma with emphasis on the various addictions. The clinical findings were noted; punch biopsy was performed followed by histological examination. Clinical and histological staging were divided into four stages, as Stages I–IV according to Khanna and Andrade classification.
Results: The 50 subjects were in the age range of 18–70 years, of which 20 patients were in clinical Group III, 15 were in histopathological stage III, 2, 1, and 2 in Stage II, Stage I, and Stage IV, respectively, out of 5 patients in clinical Group IV, 4 were in histopathological staging IV and 1 was in Stage III, out of 5 patients in clinical Group I, 3 and 2 were in histologic Stages II and I, respectively. Statistical analysis with Chi-square test showed high significance with P < 0.001.
Conclusion: The correlation of clinical and histopathological staging was found to be highly significant, thus suggesting that the subject with clinically advanced OSF had extensive fibrosis histologically.

Keywords: Areca nut, clinical staging, histopathologic staging, oral submucous fibrosis


How to cite this article:
Biradar SB, Munde AD, Biradar BC, Shaik SS, Mishra S. Oral submucous fibrosis: A clinico-histopathological correlational study. J Can Res Ther 2018;14:597-603

How to cite this URL:
Biradar SB, Munde AD, Biradar BC, Shaik SS, Mishra S. Oral submucous fibrosis: A clinico-histopathological correlational study. J Can Res Ther [serial online] 2018 [cited 2020 Jul 9];14:597-603. Available from: http://www.cancerjournal.net/text.asp?2018/14/3/597/176177




 > Introduction Top


The fast growth of industrialization, urbanization, and advances in technology has led us to live in tremendous stress. Human beings when subjected to such stress react differently and fall prey to stress relieving habits such as smoking, paan chewing, gutkha chewing, etc., as these substances have euphoric, and psychotropic activity and hence are thought to relieve stress. However, they also have detrimental effects on the body apart from being addictive. Oral cavity being the portal of entry for almost all these habits is naturally the first and most at danger.

In Indian subcontinent, the habit of paan chewing and betel nut chewing along with consumption of spicy foods is very common. They pose potential hazards to oral mucosa and can result in irreparable genetic injury. This has led to the development of premalignant lesions and conditions that may further proceed to oral cancer. One such premalignant condition most commonly seen in India is oral submucous fibrosis (OSF).

OSF is a chronic, premalignant condition of the oral mucosa which was first described by Schwartz 1952, as a condition of oral mucosa as “atrophica idiopathica mucosa oris,” later the term OSF was coined by Joshi in 1953.[1] Pindborg and Sirsat defined OSF as, “an insidious, chronic disease affecting any part of the oral cavity and sometimes the pharynx. Although occasionally preceded by and/or associated with vesicle formation, it is always associated with juxta-epithelial inflammatory reaction followed by fibroelastic change of the lamina propria, with epithelial atrophy leading to stiffness of the oral mucosa and causing trismus and inability to eat.”[2]

The condition is well recognized for its malignant potential rate of 7.6% and is particularly associated with the use of areca nut in various forms with a significant duration and frequency of chewing habits.[3]

The pathogenesis of disease is thought to be multifactorial, and chewing of areca nut has been recognized as one of the important risk factors for OSF. It has been suggested that ingestion of chilies, genetic susceptibility, nutritional deficiencies, altered salivary constituents, autoimmunity, and collagen disorders may be involved in the pathogenesis of this condition.[4]

The clinical symptoms begin with burning sensation of mucosa with hot and spicy food. Excessive salivation, blisters, ulcerations, and altered gustatory sensations follow soon. This gradually worsens to the inability of opening mouth, feeling of stiffness spreading to the tongue, the floor of mouth, and pharynx.

Depending on inter-incisal opening, symptoms and presence of palpable fibrous bands OSF are divided in different clinical stages. Depending on histological features ranging from early epithelial hyperplasia to advanced atrophy, which is always associated with juxta-epithelial inflammatory reaction and fibroelastic changes in lamina propria, OSF is again divided into a number of stages.

Treatment for OSF is a challenge, as the pathogenesis of this disease is obscure. It is said that, once the disease has developed, there is neither regression nor any effective treatment. Consequently, improved oral opening and relief of symptoms form the objective of OSF treatment. In general, the management modalities can be categorized into conservative and surgical depending on the stage of the disease.

An evaluation of the epithelial changes in the different grades of OSF showed that increase in the clinical severity of the disease may be accompanied by epithelial hyperplasia or atrophy, which is associated with an increased tendency for keratinizing metaplasia.[1] The cases may appear indolent clinically, but histopathologically may be severe. Once initiated, OSF is not amenable to reverse at any stage of the disease process even after cessation of the putative causative factor of areca nut chewing. This condition may remain either stationary or become severe, leaving an individual physically challenged, both physically and psychologically. The literature is replete with the clinicopathologic presentation of OSF. The diagnosis and staging (clinical and histological staging of OSF) thus become important as it affects the treatment and prognosis of OSF.


 > Materials and Methods Top


This study was conducted in the Department of Oral Medicine and Radiology of Rural Dental College and Hospital, Loni, Ahmednagar, Maharashtra, India. Ethical approval for carrying out this study was obtained from the Research Ethics Committee of the institute. The study population was drawn from the patients attending the outpatient Department of Oral Medicine and Radiology.

For this study, a total of 50 cases which were clinically and histopathologically diagnosed as OSF were included. All the 50 patients were male and were from the age group 18–70 years. All subjects signed the informed consent form before they were included in the study.

Exclusion criteria

  1. Patients already undergoing treatment for OSF were not included
  2. Patients with temporomandibular joint disorders sharing similar complaints of incomplete mouth opening were not included
  3. Patients with any other systemic diseases such as, anemia, scleroderma etc.


Patients were examined under artificial illumination, and the relevant data were entered into the proforma. Complete clinical history, including demographic details, various oral habits – the frequency (number of times per day), duration (years of consumption), type, duration of placement of quid and site of placement were recorded in the case history proforma.

The oral cavity was checked for all the findings of OSF, and maximum inter-incisal distance (from mesioincisal angle of upper central incisor to mesioincisal angle of lower incisor) was measured in millimeter using Digital Vernier Caliper.

The clinical staging was assessed depending on the maximum inter-incisal distance and other findings of OSF. The clinical staging was performed according to Khanna and Andrade into Stage I - very early stage - mouth opening >36 mm [Figure 1], Stage II - early stage - mouth opening 26–35 mm [Figure 2], Stage III - moderately advanced stage - mouth opening 15–25 mm [Figure 3] and Stage IVa - advanced stage - mouth opening 2–15 mm [Figure 4], Stage IVb - advanced cases with premalignant changes and malignant transformation.[5]
Figure 1: Different habits seen in OSF patients. (a) The graph shows distribution of multiple habits in OSF patients. (b) The Pie chart shows distribution of individual habits in OSF patients. (c) The graph shows distribution of duration of habits in OSF patients. (d) The graph shows distribution of frequency of habits in OSF patients

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Figure 2: Clinical staging of oral submucous fibrosis. (a) Grade I oral submucous fibrosis, (b) Grade II oral submucous fibrosis, (c) Grade III oral submucous fibrosis, (d) Grade IV oral submucous fibrosis

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Figure 3: Histopathological Stage I of oral submucous fibrosis. (a) ×10, (b) ×40

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Figure 4: Histopathological Stage II oral submucous fibrosis. (a) ×10, (b) ×40

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Necessary blood investigations required prior to biopsy were done. Local anesthesia was given, and punch biopsy was done from the most fibrosed area. The specimens were preserved in 10% formalin and sent for histopathological study.

Assessment of the histopathological staging of OSF was done according to the histologic staging of Khanna and Andrade into Grades I [Figure 5], II [Figure 6], III, and IV.[5] Then, the correlation of clinical and histopathological staging was done.
Figure 5: Histopathological Stage III oral submucous fibrosis. (a) ×10, (b) ×40

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Figure 6: Histopathological Stage IV oral submucous fibrosis. (a) ×10, (b) ×40

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Statistical analysis

Tabulation of the results was done for the OSF patients. All the variables from the study were statistically analyzed for the mean values, standard deviation, standard error, range, and “P” value. Pearson's Chi-square test was applied to find out association between variables at 5% (P = 0.05) and 1% (P = 0.01) level of significance. In all the above tests, P < 0.05 was taken to be statistically significant.


 > Results Top


The data collected were tabulated, and statistical analysis was performed. The results were tabulated [Table 1], [Table 2], [Table 3], [Table 4] and [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d.
Table 1: Distribution of patients of OSF according to the age

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Table 2: Grouping of patients of OSF according to functional and histopathological staging

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Table 3: Distribution of patients of OSF with their age with functional and histopathological staging

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Table 4: Correlation between functional and histopathological staging in patients of OSF

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 > Discussion Top


OSF, a crippling disease of the oral mucosa, evokes the interest of dental professionals in different parts of the world. It is a premalignant condition, which is seen in Indians and Southeast Asians, with overall prevalence rate in India to be about 0.2–0.5%. The peculiarity of the disease is that it is confined to a particular geographic region. This has led to the concept that dietary or cultural habits prevalent in this regions act as the etiological factors. Several studies, case reports, and reviews have explained the etiopathogenesis, clinical, and histopathological features.

A literature survey shows wide variation in age and sex distribution of OSF. Few epidemiological surveys in India have shown a male predominance. However, female predominance in the occurrence of this entity had also been shown in few studies. A study conducted in India by Sinor et al., Hazarey et al.,[6] Kiran Kumar et al.,[4] Ranganathan et al.[7] Ahmad et al.,[8] Pandya et al.,[9] Sharma et al.,[10] have shown a male predominance which is comparable to our study, but, in our study, all the patients were male (100%), which was not consistent with any of the above-mentioned studies. Male were affected in our study could be due to easy accessibility for males to use areca nut and its products more frequently than females in our society, whereas females being more conscious about their esthetic, health, and moral values, and moreover, the study was conducted in a rural area. Hence, the lifestyle is different than the urban areas.

In this study, the 50 patients were in the age range of 18–70 years, with a peak incidence in 21–30 years (68%) followed by 31–40 years (18%) and mean age being 30.1 ± 9.87 years. Hence, it can be concluded that the occurrence of OSF is seen most commonly in younger age group (21–30 years) followed by 31–40 years [Table 1]. The youngest patient was 18-year-old, and the eldest was 66-year-old. The observation of our study of peak incidence in 21–30 years, coincided with the study by Kiran Kumar et al.,[4] Pandya et al.,[9] Hazarey et al.,[6] Shivakumar and Sahana,[1] Goel et al.,[11] Angadi and Rekha.[12] The observation of our study was different from that of Pindborg and Sirsat, who reported the maximum number of OSF cases were in the age group of 40–49 years in their study. This changing trend of the disease presently indicates the involvement of more number of younger age group and this could be because of increased social encounters and economic liberty they get at this age in a rapidly developing nation like India. Therefore, during this age, they indulge in various chewing habits such as betel nut, gutka, paan masala, smoking, alcohol, etc., either to relieve stress, as a fashion or due to peer pressure.

In our study, 12% of patients had single habits, and 88% had multiple habits. Of 12%, 10% patients had gutkha chewing, which was maximum. In multiple habits group, 40% had tobacco and gutkha chewing habit, which was maximum. Other habits such as betel nut, mawa, alcohol consumption, and smoking were also seen along with tobacco and gutkha chewing, but their consumption was less as compared to gutkha and tobacco [Figure 1]. This observation shows that the impact of multiple habits for causation of OSF is more than the single habits, and the combinations of multiple habits have an additive and synergistic effect. The distribution of patients according to the individual habit in this study [Figure 1] has shown that the gutkha chewing habit was maximum i.e., 46 (38.33%) patients out of 50, followed by tobacco chewing in 40 (33.33%) patients and less patients were having the addictions of alcohol (11), betel nut (6), paan masala (6), smoking (6), and mawa (5). The mean duration of habits was found to be 4.47 ± 1.01 years, the maximum duration was 40 years, and least was 2 months [Figure 1]. The mean frequency of the habits per day was found to be 5.25 ± 0.77 times; the maximum frequency of intake was 25 times per day [Figure 1]. It can be considered by the observations of this study that the increased gutkha and tobacco chewing habit, the mean duration of 4–5 years and mean frequency of 5–6 times per day, may had led to increased prevalence of OSF in this region. From these data, it becomes evident that the gutkha, containing areca nut, tobacco as main ingredients along with lime, catechu, pan extracts, and other flavoring agents in almost all the brands available in the market may be regarded as possible prime etiological factors for inducing OSF. In this study, it was also found that the patients who chewed gutkha with a greater frequency per day developed OSF with a shorter duration of the habit. This means that the exposure to the total burden of various harmful substances in a given period, i.e., daily consumption was more significant than the total duration of the habit, however, it also depends on the individual's susceptibility. A similar observation was also reported by Maher et al.[13] who stated that the daily consumption rate appears to be much more significant with respect to risk than the life long duration of the habit. The presence of higher dry weight proportion of areca nut was responsible for the development of OSF, and this emphasizes the important role of betel/areca nut in etiology of OSF. In a study by Hazarey et al.,[6] 77.8% patients were having multiple habits, whereas 20.5% patients were having exclusive habits (only one habit), which coincided with our study. The mean frequency of chewing in Hazarey et al. study was 1.28 ± 4.03 per day and mean duration of chewing was 1.4 ± 3.59 years, which is not coinciding with this study. Men in Hazarey et al. study have shown statistically significant increase in gutkha and mawa chewing habits and females have shown an increase in areca nut habit, which is not similar to the observations of this study. These variations can be attributable to the local cultural practices, geographical variation, and easy availability of the commercial products such as gutkha and tobacco. In a study by Ahmad et al.,[8] 157 OSF patients were included and 152 patients out of 157 OSF cases used gutkha and other areca nut products, the relative number of cases who used only gutkha were more. About 55% of subjects consumed the only gutkha, which was comparable with the results of our study. Sharma et al.[10] included 231 OSF subjects, out of whom 135 (58.44%) subjects had gutkha chewing habit, 52 (22.51%) subjects chewed areca nut and tobacco and 44 (19.04%) subjects used areca nut, the presence of gutkha chewing as the most prominent habit in this study coincides with the result of our study.

The clinical staging and histopathological staging was done according to Khanna and Andrade.[5] The Khanna and Andrade [5] classification system includes both clinical and histological features of OSF, which enables to correlate the clinical severity of the disease with histopathology so that a proper treatment plan can be formulated. Shivakumar and Sahana [1] in their study of 50 patients had used this same classification for correlating clinical and histopathological staging.

In this study, clinical staging of all 50 OSF patients was assessed. It was found that maximum patients were seen in Group II and Group III (40% each) followed by Group I and Group IVA (10% each) and no patients were found in Group IVB [Table 2]. Khanna and Andrade [5] in their study of 100 OSF patients found 42 patients in Group III and 22 patients in Group II, which is comparable to our study and the number of patients were maximum in Groups III and II, and the study population was more as compared to our study. This could be because in the early cases significant changes especially, restricted mouth opening are not seen, and unless there is a significant affection of the functions of the patient's body, patients will not approach the physician, and also a lack of knowledge about the disease can also attribute to this. Shivakumar and Sahana [1] in their study of 50 patients found 18% (9) subjects in Group II, 36% (18) subjects in the Group III, 26% (13) subjects in Group I, 18% (9) subjects in Group IVA and 2% (1) in Group IVB, which is not comparable except for the increase in number of patients in Group III.

Histopathological staging of 50 subjects in this study showed, maximum patients, i.e., 27 (54%) patients were in Stage III, followed by 11 (22%) in Stage II, 9 (18%) in Stage IV and 3 (6%) in Stage I [Table 2]. Shivakumar and Sahana [1] in their study of 50 patients found Group I: 6 (12%) subjects, Group II: 22 (44%) subjects, Group III: 17 (34%) subjects, Group IV: 5 (10%) subjects and one had poorly differentiated squamous cell carcinoma. The maximum patients were in Group II followed by Group III, which is not comparable with the results of our study.

In this study, age was correlated with clinical staging [Table 3] and found maximum patients were in age group of 21–30, followed by 31–40 and significant correlation was found between age and clinical staging of OSF. It was also seen that as the age increases, the clinical staging also increases, i.e., the clinical severity of OSF increases with age. Reddy et al.[3] in their study of 390 OSF patients did not find a correlation between age and clinical stage, which did not coincide with the result of our study as the clinical staging used was different, i.e., Bailoor and Nagesh (1993).[13],[14] Kiran Kumar et al.[4] in their study in 75 OSF patients found no significant correlation between clinical staging and age, which is not comparable to our study.

Correlation of age with histopathological staging was done [Table 3] and found significant correlation and as the age increases the staging and severity increases. None of the studies had shown the correlation of age with histopathological staging.

In this study, correlation of clinical and histopathological staging [Table 4] was found to be highly significant (P < 0.001). Twenty patients in clinical Group II, maximum were in histopathological staging III (11), 20 patients in clinical Group III, maximum were in histopathological staging III (15), patients in Group IV, maximum were in histopathological staging IV, and 5 patients in clinical Group I were in histologic Stages I and II, hence, highly significant correlation was found. Shivakumar and Sahana [1] in their study found a highly significant correlation between clinical and histopathologic staging, which was consistent to our study. In a study by Kiran Kumar et al.,[4] included 75 OSF patients and found no association between clinical staging and histopathological grading. In a study by Diwakar et al.,[15] which included 50 patients, clinical staging was done according to Haider et al. and histopathological staging was done according to Rooban et al.'s criterion and found no significant correlation. Pandya et al.,[9] in their study of 239 patients, correlated histopathological diagnosis with habits and clinical findings and found no significant correlation on using grading by Pindborg and Sirsat, which was not consistent with our study. In another study by Goel et al.,[11] in Southern Rajasthan in 100 cases, did not find any significant correlation between clinical staging and histopathological grading. Similar findings were observed by Rooban et al.[16] and they concluded that the correlation between clinical staging of mouth opening and histological grading of fibrosis did not show any statistical significance. The variation in results was seen as the staging system used in our study (Khanna and Andrade, 1995) was different than other studies. Only one study (Shivakumar, Sahana) and our study used the same grading system, whereas other studies included criteria according to different authors and were the most important contributing factor for variation. Other factors that would add to this variability were the number of patients included in the studies, the use of habits were different due to geographical variation, difference in the population involved in the studies and difference in the severity and extent of fibrosis clinically in different populations.


 > Conclusion Top


In this study, the clinical staging of OSF was in relation to the histopathological staging.

Thus, it can be concluded that the clinical staging assessed by using Khanna and Andrade staging system, the clinical features of OSF would be similar to the histopathological features and hence, on the basis of clinical features, the severity of the disease can be assessed, and the patients are treated accordingly. However, in this study, the population included was not large. Hence further detailed large scale studies and researches are required so that the control of the disease would be achieved at early stages, and malignant transformation rates are reduced.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Shivakumar GC, Sahana S. Correlation between clinical and histological staging of oral submucous fibrosis. J Indian Acad Oral Med Radiol 2010;22:133-5.  Back to cited text no. 1
  [Full text]  
2.
Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966;22:764-79.  Back to cited text no. 2
[PUBMED]    
3.
Reddy V, Wanjari PV, Banda NR, Reddy P. Oral submucous fibrosis: Correlation of clinical grading to various habit factors. Int J Dent Clin 2011;3:21-4.  Back to cited text no. 3
    
4.
Kiran Kumar K, Saraswathi TR, Ranganathan K, Uma Devi M, Elizabeth J. Oral submucous fibrosis: A clinico-histopathological study in Chennai. Indian J Dent Res 2007;18:106-11.  Back to cited text no. 4
[PUBMED]    
5.
Khanna JN, Andrade NN. Oral submucous fibrosis: A new concept in surgical management. Report of 100 cases. Int J Oral Maxillofac Surg 1995;24:433-9.  Back to cited text no. 5
[PUBMED]    
6.
Hazarey VK, Erlewad DM, Mundhe KA, Ughade SN. Oral submucous fibrosis: Study of 1000 cases from central India. J Oral Pathol Med 2007;36:12-7.  Back to cited text no. 6
[PUBMED]    
7.
Ranganathan K, Devi MU, Joshua E, Kirankumar K, Saraswathi TR. Oral submucous fibrosis: A case-control study in Chennai, South India. J Oral Pathol Med 2004;33:274-7.  Back to cited text no. 7
[PUBMED]    
8.
Ahmad MS, Ali SA, Ali AS, Chaubey KK. Epidemiological and etiological study of oral submucous fibrosis among gutkha chewers of Patna, Bihar, India. J Indian Soc Pedod Prev Dent 2006;24:84-9.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Pandya S, Chaudhary AK, Singh M, Singh M, Mehrotra R. Correlation of histopathological diagnosis with habits and clinical findings in oral submucous fibrosis. Head Neck Oncol 2009;1:10.  Back to cited text no. 9
[PUBMED]    
10.
Sharma R, Raj SS, Miahra G, Reddy YG, Shenava S, Narang P. Prevalence of oral submucous fibrosis in patients visiting dental college in rural area of Jaipur, Rajasthan. J Indian Acad Oral Med Radiol 2012;24:1-4.  Back to cited text no. 10
  [Full text]  
11.
Goel S, Ahmed J, Singh M, Nahar P. Oral submucous fibrosis: A clinico-histopathological comparative study in population of Southern Rajasthan. J Carcinog Mutagen 2010;1:1-4.  Back to cited text no. 11
    
12.
Angadi PV, Rekha KP. Oral submucous fibrosis: A clinicopathologic review of 205 cases in Indians. Oral Maxillofac Surg 2011;15:15-9.  Back to cited text no. 12
[PUBMED]    
13.
Maher R, Lee AJ, Warnakulasuriya KA, Lewis JA, Johnson NW. Role of areca nut in the causation of oral submucous fibrosis: A case-control study in Pakistan. J Oral Pathol Med 1994;23:65-9.  Back to cited text no. 13
[PUBMED]    
14.
Bailoor DN, Nagesh KS. Oral Precancer. Fundamentals of Oral Medicine and Radiology. 1st ed. New Delhi, India: Jaypee Brothers Medical Publishers; 2005. p. 182-93.  Back to cited text no. 14
    
15.
Diwakar G, Arora S, Ahmed Mujib BR. A clinico-histopathological study of association between fibrosis and mouth opening in oral submucous fibrosis. J Oral Biosci 2009;51:23-30.  Back to cited text no. 15
    
16.
Rooban T, Saraswathi TR, Al Zainab FH, Devi U, Eligabeth J, Ranganathan K. A light microscopic study of fibrosis involving muscle in oral submucous fibrosis. Indian J Dent Res 2005;16:131-4.  Back to cited text no. 16
[PUBMED]  [Full text]  


    Figures

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