1. health and fitness
2. disease

Indian J Med Res 131, May 2010, pp 665-669
Efficacy of hydrocortisone acetate/hyaluronidase vs triamcinolone
acetonide/hyaluronidase in the treatment of oral submucous fibrosis
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
Received June 30, 2008
Background & objective: Oral submucous fibrosis is a common premalignant condition caused by
chewing arecanut and other irritants in various forms. Its medical treatment is not yet fully standardized,
although the optimal doses of its medical treatment is in the form of hydrocortisone acetate combined
with hyaluronidase. The problem with the prevailing treatment was injections at weekly interval. In this
study we compared the efficacy of hydrocortisone acetate and hyaluronidase at weekly interval versus
triamcinolone acetonide and hyaluronidase at 15 days interval.
Methods: Patients of OSMF (100) were randomly divided into two groups A and B. Group A patients
received combination of hydrocortisone acetate (1.5 ml)/hyaluronidase (1500 IU) at weekly interval
submucosally in pterygomandibular raphe, half dose on each side for 22 wk. Group B patients received
combination of triamcinolone acetonide (10 mg/ml)/ hyaluronidase (1500 IU) at 15 days interval for 22
wk. Treatment outcome was evaluated on the basis of improvement in symptom score, sign score and
histopathological improvement. Student’s ‘t’ test was applied for comparing the results.
Results: No statistically significant difference in symptom score, sign score and histopathological
improvement was seen between the two groups.
Interpretation & conclusion: Treatment regimen of group B was more convenient to the patients because
less number of visits required and cheap. No side effects were seen. A follow up study is required to see
long term effects.
Key words Hyaluronidase - hydrocortisone acetate - oral submucous fibrosis - tiamcinolone acetonide
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 mouth1-3. 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 stages4. In stage
1 there is stomatitis, erythematous mucosa, vesicles,
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INDIAN J MED RES, may 2010
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. Specific findings
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 deficits because of involvement of
tongue, palate and eustachian tubes5,6.
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 forms7-11. Used other methods
include injection of placental extract12, use of trypsin,
collagenase, hyaluronidase and elastase13 and intralesional
Interferon-γ (IFN-γ)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 wk18. 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 1989­4.
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 criteria19.
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
Singh et al: EFFICACY OF HYDROCORTISONE ACETATE VS TRIAMCINOLONE ACETONIDE IN OSMF
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.
Results
Patients of OSMF were between 14-65 yr old,
a majority in their 30 (average 34 yr). The male to
667
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
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 ± SD)
Score
Group A
Pre-treatment
Symptoms
Burning sensation in
336.56 ± 27.16
mouth upon
consumption of spicy
or hot foods
Repeated vesicle/
147.33 ± 15.58
formation
in oral mucosa
Sign
trismus
304.17 ± 19.58
Ankyloglossia
205.54 ± 16.67
Vesicles/Ulcers
46.26 ± 5.72
Fibrosis
680.59 ± 47.86
Total (Symtom+sign) 1707.42 ± 77.41
Score
Histopathological
39.05 ± 4.89
score
Post-treatment
Group B
Reduction in score
Pre-treatment
Post-treatment
Reduction in score
42.48 ± 7.26
294.48 ± 15.76
328.18 ± 31.43
37.67 ± 9.11
291.04 ± 16.41
22.49 ± 5.67
124.89 ± 15.24
149.71 ± 12.69
19.88 ± 6.42
129.27 ± 14.72
133.33 ± 11.48
95.47 ± 8.59
11.16 ± 2.76
360.43 ± 27.51
659.28 ± 49.87
170.42 ± 16.27
110.72 ± 17.51
35.61 ± 7.24
320.76 ± 54.76
1049.01 ± 97.14
292.59 ± 17.97
195.83 ± 19.13
44.52 ± 5.78
688.59 ± 47.46
1695.49 ± 81.57
127.35 ± 13.67
90.28 ± 9.81
10.57 ± 2.89
354.73 ± 29.21
633.48 ± 41.56
165.89 ± 15.11
105.67 ± 16.76
33.94 ± 8.41
333.86 ± 61.53
1036.01 ± 86.95
29.43 ± 3.78
9.67 ± 1.72
40.58 ± 5.06
30.55 ± 4.78
10.23 ± 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)
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INDIAN J MED RES, may 2010
Table II. Pre-treatment histopathological staging and post-treatment
histopathological staging of both group A (n=15) and group B (n=15)
Histopathological
staging
Very early
Early
Moderately
advanced
Advanced
Group A
Group B
PrePostPrePosttreatment treatment treatment treatment
0
2
0
2
6
12
5
11
9
1
10
2
0
0
0
0
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.
Discussion
Despite much progress in understanding
pathogenesis9,20 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 treatment18. 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
available10. 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
(1)
(2)
(3)
(4)
Figs 1-4. Photographs of histopathology slides of a patient from group ‘A’ (Figs 1 & 2) and group ‘B’ (Figs 3 & 4) which show change in
stage from moderately advanced to early stage.
Singh et al: EFFICACY OF HYDROCORTISONE ACETATE VS TRIAMCINOLONE ACETONIDE IN OSMF
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-γ because in the present study, mean
improvement in trismus was 18 mm in group 'B' as
compared to gain of 8±4mm with IFN-γ and there were
no side effects as compared to IFN-γ14.
In histopathological staging no patient was found
in early stage may be to the fact that we have included
only stage II cases of OSMF2. 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.
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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: [email protected]