Dr. T. Balasubramanian M.S.
Oral Submucosal fibrosis is a
chronic debilitating potentially malignant condition of the oral
cavity associated with betel nut chewing. It is characterized
by fibrosis of the oral soft tissue, resulting in marked rigidity
and inability to open the mouth. The inability to open the
mouth is slowly progressive in nature.
The term Submucosal fibrosis
was first coined by Joshi in 1952. Su termed it as
idiopathic sclerosis of mouth. Goleria in 1970 coined the term
Buccal mucosa was the most
commonly involved site, but no part of the oral cavity is immune to
this condition. Almost all the patients were pan
chewers. Pathophysiology of this disease is not well
established. A number of factors trigger the
disease process by causing a juxtaepithelial inflammatory reaction
in the oral mucosa. Factors such as areca nut chewing, ingestion of
chilies, genetic and immunologic processes, nutritional deficiencies
can lead to this condition.
Betel nut chewing: The
areca nut component used along with betel leaf has been
implicated. A recent study has clearly demonstrated the
dose and frequency relationship of areca nut chewing in the
pathogenesis of this disorder. Arecoline the active ingredient of
areca nut is known to stimulate fibroblasts to increase its
production of collagen by 150%. Flavinoids, catechin and tannin
present in betel nuts cause collagen to cross link making them less
susceptible to collagenase enzyme degradation. The disease
process of Submucosal fibrosis is active even after cessation of
betel nut chewing suggesting that arecoline not only affects the
fibroblasts it also affects gene expression in fibroblasts causing
them to produce increased amount of collagen with intense cross
Studies have also shown that
arecoline inhibits metalloproteinases (particularly
metalloproteinase 2) thus decreasing the overall breakdown of tissue
collagen. Studies have also shown that keratinocyte
growth factor-1, insulin like growth factor-1, and interleukin 6
expression, which have all been implicated in tissue fibrogenesis,
were also significantly up-regulated by arecoline. Areca
nuts are also rich in copper content. Chewing areca nuts increases
the amount of copper in the oral cavity fluids. Copper is
known to stimulate fibrinogenesis by activating copper dependent lysyl oxidase activity (suggested
Ingestion of chillies in the
pathophysiology has been controversial. Capsaicin the active ingredient of chillies have
been demonstrated to increase the level of fibrosis in rats.
Genetic factors have also been
postulated as the predisposing factor in the pathogenesis.
submucosal fibrosis have been found to have an increased frequency
of human leukocyte antigen A10 (HLA-A10), human leukocyte antigen B7
(HLA-B7), and human leukocyte antigen DR3 (HLA-DR3).
Immunologic process: have also
been implicated in the pathophysiology of submucosal fibrosis.
Increased levels of CD4 components have been demonstrated in these
patients. The number of langerhan giant cells in the site have
shown an increase.
Nutritional deficiencies: Iron
deficiency, vitamin B complex deficiency, and zinc deficiency have
also been postulated as predisposing factors. Infact these
nutritional elements are necessary for normal repair mechanism to
repair the oral mucosa which is constantly traumatized.
The morbidity and mortality of
this condition is due to the fact that the patient is unable to open
the mouth and consume normal quantities of food.
In Indian subcontinent females
out number males in the incidence of this disease. No age
group is immune to this condition. In Indian conditions in
addition to the irritant effects of arecoline the nutritional
deficiencies also play an important role in the pathogenesis of this
1. Progressive inability to
open the mouth due to fibrosis and scarring
2. Oral pain and burning
sensation when the patient consumes spicy food
4. Change in
5. Secretary otitis media due
to stenosis of the pharyngeal end of Eustachian tube
6. Dryness of
7. Dysphagia when consuming
solids if esophagus is involved
Various stages of submucosal
Stage I: Stomatitis,
erythematous mucosa, vesicles, melanotic pigmentation of the oral
mucosa, and mucosal petechia.
Stage II: Fibrosis begin with
rupture of vesicles and healing of oral ulcers. Early lesions
show blanching of the involved oral mucosa. Older lesions include vertical and circular
palpable fibrous bands in the buccal mucosa and around the mouth
opening or lips, resulting in a mottled marble like appearance of
the mucosa because of the vertical, thick, fibrous bands running in
a blanching mucosa. There is reduction of mouth opening in
this stage, the tongue is stiff and small, the floor of the mouth
has a blanched leathery appearance. The gingiva appears
fibrotic and depigmented, the soft palate is rubbery with decreased
mobility. The anterior and posterior pillars of the tonsils
are pale and the tonsils also show atrophy. The uvula appear
(premalignant condition) is a feature of this stage. Speech
and hearing defects are also common in this stage
Khanna grouped these patients
according to the degree of trismus to facilitate decision making
regarding the management issues involved.
First degree: is the earliest
stage. These patients do not have mouth opening
difficulties. The only feature being the blanching seen in the
oral mucosa associated with burning sensation on consuming spicy
Second degree: These patients
have a mouth opening of 26 - 35 mm
Third degree: These are
moderately advanced cases with mouth opening of 15 - 25 mm.
Fibrotic bands are seen in the soft palate, anterior pillars of
tonsils, and pterygo mandibular raphe.
Fourth degree: Most advanced
case with severe trismus, presence of leukoplakia. This is
infact a premalignant condition.
No specific lab study is
Very early stage: is
characterized by the presence of fine fibrillar collagen, marked
oedema, large fibroblasts, large congested blood vessels with acute
inflammatory reaction cells around it.
Early stage: is characterized
by the thickening of the collagen bundles, increase in the number of
fibroblasts and inflammatory cells.
Advanced stage: Collagen sheets
form dense bundles, thick bands of subepithelial hyalinization occur
in the submucosal tissue, there is decreased vascularity, and
chronic inflammatory cells are seen. Chronic inflammation of
minor salivary glands are also seen. This is the stage
associated with severe trismus.
Medical: Weekly Submucosal
intralesional injections of steroids may help in prevention of
progression of the disease. Cessation of betel nut chewing is
a must. Placental extracts can be injected intra lesionally to
reduce the inflammatory effects of the disease. Use of topical
hyaluronidase in doses of 150 units in association with steroids has
Intralesional injection of
IFN-gamma has a role due to the
immuno regulatory effect of the molecule.
Surgical management is reserved
only for advanced cases with severe trismus. This include
excision of fibrous bands, with split thickness skin grafting.
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