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Efficacy of hydrocortisone acetate/hyaluronidase vs triamcinolone acetonide/hyaluronidase in the treatment of oral submucous fibrosis.

Oral submucous fibrosis (OSMF) is a chronic debilitating and a well recognized potentially malignant condition of oral cavity associated with arecanut chewing characterized by generalized fibrosis of oral soft tissue resulting in marked rigidity and progressive inability to open the mouth (1-3). This disease is mainly confined to South East Asian countries especially in the Indian subcontinent. Pathogenesis is not yet established but it is believed to be due to multifactorial causes. The disease initially presents as burning sensation in oral cavity. It is clinically divided into three stages (4). In stage 1 there is stomatitis, erythematous mucosa, vesicles, mucosal ulcers, melanotic mucosal pigmentation and mucosal petechiae. In stage 2, fibrosis occurs in ruptured vesicles and ulcers when they heal. There is blanching of oral mucosa. Vertical and circular palpable fibrotic bands are seen in buccal mucosa. Speciic indings include trismus, stiff and small tongue, blanched and leathery floor of mouth, fibrotic and depigmented gingiva, rubbery soft palate with decreased mobility, blanched and atrophic tonsils, shrunken band like uvula and sinking of cheek not commensurate with age or nutritional status. In stage 3 there are sequelae in the form of leukoplakia in about 25 per cent of cases, speech and hearing deicits because of involvement of tongue, palate and eustachian tubes (5,6).

Most important aspect of medical treatment is cessation of habit of eating betel quid, arecanut, other local irritants, spicy and hot food, alcohol and smoking. The most common mode of medical treatment had been the use of steroids in its various forms (7-11). Used other methods include injection of placental extract (12), use of trypsin, collagenase, hyaluronidase and elastase (13) and intralesional Interferon-[gamma] (IFN-[gamma])14. Oral zinc has been used15 as also oral pentoxiphylline16 and lycopene with varying benefits17.

Local injection of hyaluronidase mixed with hydrocortisone acetate had been used at our centre for the last 20 ys with satisfactory clinical results and without any significant side effects. The problem with the treatment was that the doses and duration of treatment had not been standardized. In a previous study, the treatment regimen was standardized with patients of OSMF with trismus be treated by 1.5 ml (37.5 mg) hydrocortisone acetate mixed with 1500 IU of hyaluronidase injection given intralesionally half dose on each side at weekly interval for 22 wk (18). The problem with prevailing treatment was injection at weekly interval. So, this study was planned to see the efficacy of this treatment as compared to triamcinolone acetonide (10 mg/ml) combined with hyaluronidase (1500 IU) intralesionally once in 15 days for a total of 11 injections.

Material & Methods

This prospective randomized single blinded outcome based study was done on 100 cases of clinically diagnosed oral submucous fibrosis done during 2005-2006. Clinical diagnosis of OSMF was based on symptom of burning sensation in mouth upon consumption of spicy or hot foods, repeated vesiculation or ulceration in oral cavity and signs observed were vesicles/ulcers in oral cavity, areas of fibrosis in vestibule of mouth, oral cavity proper and oropharynx, partial or complete inability to protrude out the tongue (ankyloglossia) with or without reduced mouth opening (trismus). After diagnosis staging was done according to the criteria of Pindborg 1989 (4). Patients of stage II OSMF having trismus were included in this study. Stage I and III were excluded. Trismus was defined as mouth opening less than normal. Normal mouth opening was interincisor distance of 5.25 cm in males and 4.75 cm in females as measured by a caliper. All patients were properly explained about the study and their consent was taken. The study was cleared by Institutional Review Board.

The symptoms and signs were noted on a working proforma. Scoring of symptoms like burning sensation in mouth upon consumption of spicy or hot foods and repeated vesicles or ulcer formation was done according to verbal complaint rating scale of 0-10 points, where 0 means no symptom and 10 means severe most symptom as perceived by the patient subjectively and signs were scored from 0 to 10 points according to a new criteria. Trismus was scored as 0 means no trismus where interincisor distance was 5.25 cm or more in males and 4.75 cm or more in females, scored as 2 or grade I where interincisor distance was more than 3 cm but less than normal, scored as 5 or grade III where interincisor distance was 2-3 cm and scored as 10 where interincisor distance was less than 2 cm. Ankyloglossia was scored as 5 when protrusion of tongue was partial and scored 10 when there was inability to protrude out the tongue. Vesicles or ulcers in oral cavity were scored 1 when there were unilateral single, scored 2 when bilateral single, scored 3 when unilateral multiple and scored 4 when bilateral multiple. Areas of fibrosis were scored 2 for each area--soft palate including uvula, right or left anterior faucial pillar including tonsil, right or left buccal mucosa including gingivobuccal sulcus, right or left retromolar trigone, tongue or floor of mouth.

The pretreatment histopathological examination of the biopsy specimen from cheek mucosa was done in each case and histopathological staging of OSMF was done according to Pindborg and Sirsat criteria (19).

All the four histopathological stages viz., very early, early, moderately advanced and advanced stage were given scores of 1, 2, 3 and 4 respectively. Patients were randomly divided into group A and B according to a lottery system by keeping a mixture of 50 chits each of group 'A' and group 'B'. Patients were asked to pick up one chit and his treatment group was decided. Patients of group 'A' (n=50) were treated by a combination of hydrocortisone acetate (1.5 ml 25 mg/ml) and hyaluronidase (1500 IU) at weekly interval for 22 wk and group 'B' were treated by a combination of triamcinolone acetonide, 10 mg/ ml and hyaluronidase (1500 IU) at 15 days interval for 22 wk, i.e. 11 injections in 22 wk. Injection in all patients were given submucosally in retromolar trigone and adjacent soft palate and cheek, half dose on each side by one observer and response to treatment was assessed by another observer. The other clinician who was observing response to treatment was not aware of the treatment group. After completion of treatment, repeat biopsy and histopathological examination was done to look for histopathological improvement. The histopathologist who was evaluating post-treatment biopsies was not aware of the treatment group. The response to treatment was assessed by noting subjective improvement in symptom score, objective improvement in sign score and histopathological score. Side effects of treatment both local as well as systemic e.g., weight gain, blood pressure etc., were also noted. Period of post-treatment follow up was three months. All the registered patients were followed up.


Patients of OSMF were between 14-65 yr old, a majority in their 30 (average 34 yr). The male to female ratio was 6.14:1. 71 per cent were in the habit of using pan masala or dohra. Only 22 per cent used them with betel quid and 7 per cent used betel quid only. Pre-treatment histopathological staging showed most patients in moderately advanced stage (55%) followed by early stage (43%) and advanced stage (2%).

All the patients who were registered were followed up for 3 months after completion of treatment. There were no dropouts. All the patients were aware of the fact that they are being treated for a pre-cancerous lesion. There was no delay from diagnosis to commencement of therapy. But many patients although initially agreed for a post-treatment biopsy, refused biopsy after completion of treatment.

Table I shows pre-treatment and post-treatment symptom and sign scores, improvement in total (i.e. symptom + sign) score and histopathological score in group A and B. A comparison between both groups did not provide any statistically significant difference (P>0.05).

Table II shows the details of change in histopathological stage of OSMF in both treatment groups. Figs 1 and 2 show the photograph of histopathology slides of a patient from group 'A' which shows change in stage from moderately advanced to early stage and Figs 3 and 4 showed similar change in group 'B'. No local or systemic side effects were found in either treatment groups.


Despite much progress in understanding pathogenesis (9,20) treatment of OSMF in the absence of properly designed trials and lack of standardized doses and duration of treatment we had standardized and recommended the treatment (18). The problem with this treatment was injections at weekly interval. Triamcinolone acetonide is a better corticosteroid for intralesional injection as it has better local potency, longer duration of action and lesser systemic absorption. It was hypothesized that if it will be given at 15 days interval as in the treatment of keloid and hypertrophic scar, then it will be convenient to the patients. However, there was not a single big study. Only case reports were available (10). We had followed a new scoring system in which each symptom, sign and histopathological stage of OSMF was given a particular score before and after completion of therapy. Objectivity of the study was thus increased by observing improvement in symptom score and by measuring pre and post-treatment interincisor distance with a caliper and seeing histopathological improvement. None of the previous studies had used this type of outcome measures. It is clear from our study that there was statistically significant improvement in symptom score, sign score, histopathological score in both groups after treatment and further there was no statistically significant difference in outcome in both groups 'A' and 'B'. There were no side effects in either group. Therefore, it is obvious that both treatment regimens have similar outcome. Treatment regimen of group 'B' is more convenient to the patient's because it requires less number of visits to the consultants and, therefore, it is cheaper also. Hence it is recommended that triamcinolone acetonide (10 mg/ml) combined with 1500 IU of hyaluronidase should be given intralesionally particularly in retromolar trigone area half dose each side at 15 days interval for a total of 11 injections in 22 wk. This treatment regimen was better than IFN-[gamma] because in the present study, mean improvement in trismus was 18 mm in group 'B' as compared to gain of 8[+ or -]4mm with IFN-[gamma] and there were no side effects as compared to IFN-[gamma] (14).


In histopathological staging no patient was found in early stage may be to the fact that we have included only stage II cases of OSMF (2). Total improvement in histopathological score in group 'A' and 'B' was 9.67+1.72 and 10.23+2.05 respectively. None of the earlier study looked at post treatment histopathological changes. Our study some shortcomings like long term effects after completion of therapy could not be done.

Received June 30, 2008


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(2.) Aziz SR. Oral submucous fibrosis: an unusual disease. JNJ Dent Assoc 1997; 68: 17-9.

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(4.) Pindborg JJ. Oral submucous fibrosis: a review. Ann Acad Med Surg 1989; 18: 603-7.

(5.) Khanna S. Histological changes in palatal and paratubal muscles in oral submucous fibrosis. MS thesis, University of Allahabad; 1999.

(6.) Chaturvedi R. To study the Eustachian tube function in patients of oral submucousfibrosis. MS thesis, University of Allahabad; 2003.

(7.) Rao V, Raju PR. Treatment of SMF with cortisone. Indian J Otolaryngol 1954; 6: 81-3.

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(10.) Hamner JE 3rd, Looney DD, Chused TM. Submucous fibrosis. Oral Surg Oral Med Oral Pathol 1974; 37: 412-21.

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(13.) Sirsat SM, Khanolkar VR. Histological, electron microscope and enzyme studies of submucous ibrosis of the palate. J Pathol Bacteriol 1960; 79: 53-8.

(14.) Haque MF, Meghji S, Nazir R, Harris M. Interferon gamma (IFN -gamma) may reverse oral submucous fibrosis. J Oral Pathol Med 2001; 30: 12-21.

(15.) Kumar A. Sharma SC, Sharma P, Chandra OM, Singhal KC, Nagar A. Beneficial effect of oral zinc in the treatment of oral submucous ibrosis. Indian J Pharmac 1991; 23: 236-41.

(16.) Rajendran R, Rani V, Shaikh S. Pentoxifylline therapy: new adjunct in the treatment of oral submucous ibrosis. Indian J Dent Res 2006; 17: 190-8.

(17.) Kerr AR Eficacy of oral lycopene in the management of oral submucous ibrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103: 214-5.

(18.) Kinger A. To study the optimal dosage of hydrocortisone acetate and hyaluronidase in the treatment of oral submucous fibrosis. MS thesis, University of Allahabad; 2004.

(19.) Pindborg JJ, Sirsat SM. Oral submucous ibrosis. Oral Surg Oral Med Oral Pathol 1966; 22: 764-79.

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Reprint requests: Dr Mangal Singh, Professor, Department of ENT & Head & Neck Surgery, M.L.N Medical University College & S.R.N. Hospital, Allahabad 211 001, India e-mail:

Mangal Singh, H.S. Niranjan, Ravi Mehrotra*, Devashish Sharma** & S.C. Gupta

Departments of E.N.T. & Head & Neck Surgery, * Pathology & ** Statistics & Demography, M.L.N. Medical University College & S.R.N. Hospital, Allahabad, India
Table I. Pre treatment and post-treatment symptom and sign score,
improvement in total (i.e. symptom + sign) score and
histopathological score in group 'A' (n=50) and group B (n=50)
(Data are mean [+ or -] SD)


 Group A

 Pre-treatment Post-treatment

Burning sensation in 336.56 [+ or -] 27.16 42.48 [+ or -] 7.26
 mouth upon
 consumption of
 spicy or hot foods
Repeated vesicle/ 147.33 [+ or -] 15.58 22.49 [+ or -] 5.67
 in oral mucosa
Trismus 304.17 [+ or -] 19.58 133.33 [+ or -] 11.48
Ankyloglossia 205.54 [+ or -] 16.67 95.47 [+ or -] 8.59
Vesicles/Ulcers 46.26 [+ or -] 5.72 11.16 [+ or -] 2.76
Fibrosis 680.59 [+ or -] 47.86 360.43 [+ or -] 27.51
Total (Symtom+sign) 1707.42 [+ or -] 77.41 659.28 [+ or -] 49.87
Histopathological 39.05 [+ or -] 4.89 29.43 [+ or -] 3.78


 Group A Group B

 Reduction in score Pre-treatment

Burning sensation in 294.48 [+ or -] 15.76 328.18 [+ or -] 31.43
 mouth upon
 consumption of
 spicy or hot foods
Repeated vesicle/ 124.89 [+ or -] 15.24 149.71 [+ or -] 12.69
 in oral mucosa
Trismus 170.42 [+ or -] 16.27 292.59 [+ or -] 17.97
Ankyloglossia 110.72 [+ or -] 17.51 195.83 [+ or -] 19.13
Vesicles/Ulcers 35.61 [+ or -] 7.24 44.52 [+ or -] 5.78
Fibrosis 320.76 [+ or -] 54.76 688.59 [+ or -] 47.46
Total (Symtom+sign) 1049.01 [+ or -] 97.14 1695.49 [+ or -] 81.57
Histopathological 9.67 [+ or -] 1.72 40.58 [+ or -] 5.06


 Group B

 Post-treatment Reduction in score

Burning sensation in 37.67 [+ or -] 9.11 291.04 [+ or -] 16.41
 mouth upon
 consumption of
 spicy or hot foods
Repeated vesicle/ 19.88 [+ or -] 6.42 129.27 [+ or -] 14.72
 in oral mucosa
Trismus 127.35 [+ or -] 13.67 165.89 [+ or -] 15.11
Ankyloglossia 90.28 [+ or -] 9.81 105.67 [+ or -] 16.76
Vesicles/Ulcers 10.57 [+ or -] 2.89 33.94 [+ or -] 8.41
Fibrosis 354.73 [+ or -] 29.21 333.86 [+ or -] 61.53
Total (Symtom+sign) 633.48 [+ or -] 41.56 1036.01 [+ or -] 86.95
Histopathological 30.55 [+ or -] 4.78 10.23 [+ or -] 2.05

Comparison between mean reduction of score between Group A and Group
B shows no statistical significant difference between symptoms, sign
score, improvement in total (symptom + sign) score and
histopathological score (P>0.05)

Table II. Pre-treatment histopathological staging and post-treatment
histopathological staging of both group A (n=15) and group B (n=15)

 Group A Group B

Histopathological Pre- Post- Pre- Post-
staging treatment treatment treatment treatment

Very early 0 2 0 2
Early 6 12 5 11
Moderately 9 1 10 2
Advanced 0 0 0 0
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Article Details
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Author:Singh, Mangal; Niranjan, H.S.; Mehrotra, Ravi; Sharma, Devashish; Gupta, S.C.
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:9INDI
Date:May 1, 2010
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