7 Osmf

Oral Submucous Fibrosis
Premalignant Lesions and Conditions 33

3

Oral submucous fibrosis (OSF) is a chronic,
progressive, scarring disease, that predominantly affects
people of South-East Asian origin. This condition was
described first by Schwartz (1952) while examining five
Indian women from Kenya to which he ascribed the
descriptive term "atrophia idiopathica (tropica) mucosae
oris". Later in 1953, Joshi from Bombay (Mumbai)
redesignated the condition as oral submucous fibrosis;
imply predominantly its histological nature.

The WHO definition for an oral precancerous
condition -a generalized pathological state of the oral
mucosa associated with a significantly increased risk
cancer-accords well with the characteristics OSF
19
.

Thus it is a chronic insidious disease affecting any
part of the oral cavity occasionally preceded by or
associated with vesicle formation, associated with juxta
epithelial inflammation followed by fibro-elastic change of
the lamina propria with epithelial atrophy leading to
restricted mouth opening, resulting as trismus leading t
restriction of food consumption, difficulty in maintaining
oral healthoral health, as well as impairs the ability to
speak ( Pindborg JJ and Sirsat SM, 1966) .
24


Etiology:
There is evidence to implicate the habitual chewing of
areca nut with the development of OSF. It occurs
predominantly in the Indian subcontinent where the habit is
more prevalent.
Constituents of Betel Quid:
Quid is defined as a ' substance or mixture of
substances, placed in the mouth or chewed and remains in
contact with the mucosa, usually containing one or both of
the two basic ingredients , tobacco and /or areca nut, in raw
or any manufactured or processed form.

Betel quid is mixture of areca nut (betel nut), slaked
lime, catechu, and several condiments according to taste
wrapped in a betel leaf.

Major areca nut alkaloids are arecoline,
arecolidine, guyacoline, and guacine. The important
flavinoid components of areca nut are tannins and
catechins. Arecoline is the most abundant alkaloid amongst
all. These alkaloids undergo nitrosation and give rise to
N-Nitrosamine, which might have cytotoxic effect on cells.

OSF may be related to peculiar dietary components,
chillies (capsicum), a strongly irritating spice
commonly used in India .
Nutritional deficiencies such as deficiency of vitamin
B12, folate and iron can affect the integrity of the oral
mucosa.

Pathogenesis:
Previous studies on the pathogenesis of OSF have
suggested that the occurrence may be due to,
Stimulation of fibroblast proliferation and
collagen synthesis by areca nut alkaloids
(Harvey W, et al. 1986)
Clonal selection of fibroblasts with a high amount of
collagen production during the long-term exposure
to areca quid ingredients (Meghji S, et al, 1987)
By stabilization of collagen structure by catechin
and tannins from the areca nut (Scutt A, et al, 1987)
By decreased secretion of collagenase (Shieh TY, et
al. 1992)
By production of collagen with a more stable structure
(collagen type I trimer) by OSF fibroblasts (Kuo
MYP, etal, 1995)
By an increase in collagen cross-linkage as caused by
up regulation of lysyl oxidase by OSF fibroblasts (Ma
RH, et al. l995). A disturbance of collagen cross-
linking may be involved in OSF pathogenesis.
However, susceptibility to OSF could involve
multigenic mechanisms modified by the betel quid-
exposure dose in OSF induction
20
.
Genetic susceptibility may also be associated with
OSF because raised frequencies of HLA-AlO. - B7 and
- DR3 are found in OSF patients compared
to normal subjects. (Saeed B, et al, 1997).
Deficiency in collagen phagocytosis by OSF
fibroblasts (Tsai CC, et al, 1999).

By fibrogenic cytokines secreted by activated
macrophages and T lymphocytes in the OSF tissues .
(Haque MF, et al, 2000).
High copper content in areca nut plays a vital role in
pathogenesis of OSF. High levels of copper in
areca nuts, a major etiological factor in OSMF plays
an initiating role in stimulation of fibrinogenesis and
by up regulation of lysyl oxidase and thereby causing
inhibition of degradation of collagen and causing its
accumulation thereby causing OSMF. The rise in
serum copper may be due to increased turnover of
ceruloplasmin in the serum of carcinoma patients
21, 22
.
Depletion of glutathione which occurs through
glutathione-S-transferase reaction is associated with
cell damage and increased susceptibility to toxic
challenge which is responsible for cytotoxicity in
pathogenesis of OSF
24
.
OSMF occurs as a consequence of disturbances in the
homeostatic equilibrium between synthesis and
degradation of ext racellular matrix (ECM), wherein
collagen forms a major component, thus can be
considered as a collagen-metabolic disorder.
Transforming growth factor-beta (TGF-beta) is a
potent stimulator of production and deposition of the
ECM.
Increased and continuous deposition of extracellular
matrix may take place as a result of disruption of the
equilibrium between matrix metalloproteinases

(MMPs) and tissue inhibitors of matrix
metalloproteinases (TIMP)
19, 22
.

Molecular pathogenesis
24
:
I. Initial events of the disease process:
Oral mucosa which is in direct contact with betel
quid, is the site of constant irritation. This results in a
chronic inflammatory process characterised by the presence
of inflammatory cells like T cells and macrophages. These
cells release and / or stimulate the synthesis of various
cytokines such as Interleukin 6 (IL-6), Tumor necrosis
factor (TNF), Interferon - alpha (IF- alpha) and growth
factors such as transforming growth factor (TGF-beta ).

II. Collagen production pathway:
This is regulated by TGF-beta which has autocrine
activity. This activates pro-collagen genes, resulting in
more production of pro-collagen. It also induces the
secretion of pro-collagen proteinase (PCP) and pro-collagen
N-proteinase (PNP), both of which are required for the
conversion of pro-collagen to collagen fibrils.

In OSF, there is increased cross -linking of
collagen, resulting in increased insoluble form. This is
facilitated by the increased activity and production of a key
enzyme lysyl oxidase (LOX).


Role of LOX:
LOX is an essential enzyme for final processing of
collagen fibers in to a stabilized covalently cross -linked
mature fibrillar form that is resistant to proteolysis. LOX is
dependent on copper for functional activity. Pro-collagen
proteinase, bone morphogenetic protein 1, increased copper
and flavinoids in betel quid stimulate LOX activity.
Increased levels and activity of LOX causes increased
cross-linking of collagen fibres, tilting the balance towards
a fibrotic condition.


III. Collagen degradation pathway:
Two main events are modulated by TGF-beta, which
decreases the collagen degradation:
Activation of tissue inhibitor of matrix
metalloproteinase gene (TIMPs)
Activation of plasminogen activator (PAI) gene
TGF-beta activates the genes for TIMPs; thereby more
TIMP is formed. This inhibits the activated
collagenase enzyme that is necessary for degradation
of collagen. It also activates the gene for PAI, which
is the inhibitor of nlasminogen activator, thus there is
no plasmin formation, plasmin is required for the
conversion of pro-collagenase and absence of plasmin
results in active collagenase. Along with this,
flavinoids present in areca nut also inhibits the
collagenase activity. The inhibition of the exist ing
collagenase and decreased generation of active
collagenase together results in a marked decrease in
collagen degradation and resultant build up of
collagen in OSF.



A light microscopic study was done of fibrosis involving
muscles in oral submucous fibrosis
25
:
The fibrosis was graded as
Stage 1: Fibrosis limiting to laminapropria alone
Stage 2: Fibrosis involving superficial region of
muscle bundle
Stage 3: Fibrosis involving deeper regions of muscle
bundle
Stage 4: Muscle bundle replaced by fibrosis.

Classification based on Clinical features
26
:
l. Pindborg JJ (1989)
Pindborg divided OSMF based on physical findings in
to 3 stages as follows,
Stage 1: Stomatitis includes erythematous mucosa ,
vesicles, mucosal ulcers, melanotic mucosal
pigmentation, and mucosal petechiae.
Stage 2: Fibrosis occurs in healing vesicles and ulcers
which is the hall mark of this stage.
Stage 3: Sequelae are as follows:
Leukoplakia is found in more than 25% of
individuals with OSMF.
Speech and hearing deficits may occur
because of involvement of tongue and the
Eustachian tubes.

2. Lai DR et al (1995)
Lai DR et al divided OSMF population based on inter -
incisal distance,
Group A: Mouth opening greater than 35 mm.
Group B: Mouth opening between 30-35 mm.
Group C: Mouth opening between 20-30 mm.
Group D: Mouth opening less than 20 mm.

3. Ranganathan k et al (2001)
Ranganathan et al used a baseline study on mouth
opening parameters of normal patients and divided the
OSMF patients as

Group I: Only symptoms with no demonstrable
restriction of mouth opening.
Group II: Limited mouth opening. 20 mm and above.
Group III: Mouth opening less than 20 mm.
Group IV: OSMF advanced with limited mouth
opening. Pre-cancerous or cancerous changes
seen throughout the mucosa.

4. Rajendran R (2003)
Early OSF: Burning sensation in the mouth. Blisters
especially on the palate, ulceration or recurrent generalized
inflammation of the oral mucosa, excess salivation,
defective gustatory sensation and dryness of the mouth.

Advanced OSF: Blanched and slightly opaque mucosa,
fibrous bands in buccal mucosa running in vertical
direction. Palate and the faucial pillars are the areas that
are first involved. Gradual impairment of tongue movement
and difficulty in mouth opening.

Clinical Features
2, 19
:
The onset is insidious, over two to five years.

Early OSF( Prodromal Symptoms):
This includes a burning sensation in the mouth when
consuming spicy food, appearance of blisters especially on
the palate, ulcerations or recurrent generalized
inflammation of the oral mucosa, excessive salivation,
defective gustatory sensation and dryness of the mouth.

There are periods of exacerbations manifested by the
appearance of small vesicles in the cheek and palate. The
intervals between such exacerbation vary from three months
to one year.

Focal vascular dilatations manifest clinically as
petechiae in the early stages of the disease. This may part
of a vascular response due to hypersensitivity of the oral
mucosa towards some external irritant like areca nut
products. Petechiae are observed, mostly on the tongue
followed by labial and buccal mucosa with no sign of blood
dyscrasias or systemic disorders.

Pain in areas where sub mucosal fibrotic
bands are developing when palpated is a useful clinical
test.

Histological Features:
The oral mucosa reveals a slightly
hyperplastic epithelium, sometimes atrophic with
numerous blood-filled capillaries juxtaepithelially.
The inflammatory cells seen are mainly
lymphocytes, plasma cells and occasional eosinophils.
The presence together of large numbers of
lymphocytes and fibroblasts as well as plasma cells in
moderate numbers, suggests the importance of a
sustained lymphocytic infiltration in the tissue
reaction of oral submucous fibrosis.


Advanced OSF:
As the disease progresses, the mucosa becomes
blanched and slightly and white fibrous bands appear.
The buccal mucosa and lips may be affected at an
early stage, although it was thought that the palate and
the faucial pillars are the areas involved first.
The oral mucosa is involved symmetrically and the
fibrous bands in the buccal mucosa run in a vertical
direction. The density of the fibrous deposit varies
from a slight whitish area on the soft palate, causing
no symptoms, to a dense fibrosis, causing fixation and
shortening or even deviation of the uvula and soft
palate.
The fibrous tissue in the faucial pillars ranges from a
slight submucosal accumulation in both pillars to a
dense fibrosis extending deep into the pillars with
strangulation of the tonsils. It is this dense fibrosis,
involving the tissues around the pterygomandibular
raphae, that causes varying degrees of difficulty in
mouth opening sometimes fibrosis spreads to the
pharynx and to the piriform fossae.
A circular band may be palpable around the rima oris
and these changes are marked in the lower lip.
Impairment of tongue movement in patients with
advanced OSF with significant atrophy of the tongue
papillae.
With progressing fibrosis, the stiffening of certain
areas of the mucosa occurs leading to difficulty in
opening the mouth, inability to whistle or blow out a

candle and difficulty in swall owing. When the fibrosis
involves the nasopharynx, the patient may experience
referred pain to the ear and a nasal voice as one of the
later signs in some patients.
Progression of fibrosis as sequelae of the disease
process in and around the muscle as well in the region
of neurovascular bundles could cause functional and
nutritional impairment. Due to the compression of
muscle bundle along with neuromuscular bundles by
thick collagen fibers, the myofibres suffers damage.
Compartmentalization of muscle tissues by dense
collagen may cause myoischemia. The fibrosis makes
the muscle more susceptible for repeated injury upon
function. The role of such repeated muscle trauma and
the consequent micro hemorrhages could not be
underestimated
27
.

Histopathological classification
28
:
On the basis of the histopathological
appearance of stained H&E sections, Pindborg JJ and
Sirasat SM (1966) were first to divide OSF into four
clearly definable stages:
Very early stage: Finely fibrillar collagen
dispersed with marked edema. Plump young
fibroblast containing abundant cytoplasm. Blood
vessels are dilated and congested. Inflammatory cells,
mainly polymorphonuclear leukocytes with occasional
eosinophils are found.

Early stage: Juxta-epithelial area shows hyalinization.
Collagen still in separate thick bundles. Moderate
number of plump young fibroblasts is present. Dilated
and congested blood vessels. Inflammatory cells are
primarily lymphocytes, eosinophils, and occasional
plasma cells.
Moderately Advanced stage: Collagen is moderately
hyalinized. Thickened collagen bundles are separated
by slight residual edema. Fibroblastic response is less
marked. Blood vessels are either normal or
compressed. Inflammatory exudate consists of
lymphocytes and plasma cells.
Advanced stage: Collagen is completely hyalinized.
Smooth sheets with no separate bundles of collagen
are seen. Edema is absent. Hyalinized area are devoid
of fibroblasts. Blood vessels are completely
obliterated or narrowed. Inflammat ory cells are
lymphocytes and plasma cells.

These stages are based not only on the amount and
nature of the sub epithelial collagen, but also on the
following criteria taken together.
a) Presence or absence of edema,
b) Physical state of the mucosal collagen,
c) Overall fibroblastic response,
d) State of the blood vessels, and
e) Predominant cell type in the inflammatory exudates.


Utsunomiya H, Tilekratne WM, Oshiro K et al (2005):
Divided OSF histologically based on the concept of
Pindborg and Sirasat and modified it as
1. Early stage
2. Intermediate stage
3. Advanced stage

A vascular response due to inflammation, apart from
the connective tissue repair process, has been very
commonly found in OSF. Normal, dilated and constricted
blood vessels have been seen often in combination, in the
same section.

The apparent narrowing of the smaller vessels appears
first in the upper mucosa and spreads gradually to the
larger, deeper vessels. Persistent dilatation has also been
seen in many moderately advanced bi opsies. A rise in mast
cells occurs in the earlier stages of the tissue reaction but in
advanced stages, the counts are fewer in number.

The inflammatory cells seen are mainly lymphocytes
and plasma cells. The connective tissue in advanced stages
is characterized by the submucosal deposition of extremely
dense and avascular collagenous tissues with variable
numbers of chronic inflammatory cells.

The excessive fibrosis followed by hyalinization in
the mucosa seems to be the primary pathology in OSF. The
atrophic changes in the epithelium are secondary.


Biological Studies on Individuals and Tissues from
OSF Blood chemistry and hematological variations
20
.
Deficiency of vitamin B12, folate and iron can affect
the integrity of the oral mucosa. Significant hematological
abnormalities have been reported in OSF, including an
increased blood sedimentation rate (ESR), anemia and
eosinophilia, increased gamma-globulin, a decrease in
serum iron and an increase in total iron binding capacity
(TIBC). The percentage saturation of transferrin also
decreased and a significant reduction in total serum iron
and in albumin was found.

A rise in serum mucoproteins, mucopolysaccharides
and anti-streptolysin titre ' 0' (measured in Todd' s unit) has
also been reported. A significant depression of the lactate
dehydrogenase, iso-enzyme ratio (LDH IV / LDH II) is
reported at the tissue level in OSF. A significant alteration
in the serum copper and zinc ratio is also reported with a
reduction in zinc content.

Chromosomal instability has long been associated
with the neoplastic process and the quantitative
assay of sister chromatid exchange (SCE) provides an
easy, rapid and sensitive method for studying chromosome
DNA instability and its subsequent repair processes. This
increase may be attributed to the genotoxic effect of the
constituents of betel quid. The role of areca nut alkaloids in
this regard may be significant.

Ag NOR.
Silver-binding nucleolar organizer region proteins (Ag
NORs) comprise a si mple and reproducible cytological test
indicative of the proliferative status of cells, particularly of
epithelial and hematopoetic origin. It was found that the
pooled mean AgNOR count in clinically advanced OSF was
higher than in moderately advanced cases. Counting of Ag
NORs may be useful as a predictor of the biological
behavior of OSF.

Immunological studies
The suggestion of Canniff et al., (1981) that the
human leukocyte antigens (HLA) A10, B7 and DR3
occurred significantly more frequently in OSF i s important.

Management
2, 20
.
The reduction or even elimination of the habit of areca
nut chewing is an important preventive measure. At least in
the early stages of OSF it could probably slow the progress
of the Disease.

To improve current treatment regimens of OSF the
following strategies have been proposed.

(a) Nutritional support.
Mainly for high proteins and calories and for vitamin
B complex and other vitamins and minerals.


(b) I mmunomodulatory drugs.
Local and systemic applications of glucocorticoids
and placental extracts are commonly used. These also
prevent or suppress inflammatory reaction, thereby
preventing fibrosis by decreasing fibroblastic proliferation
and deposition of collagen.

Local glucocorticoids: Hydrocortisone along with procaine
hydrochloride injection in area of fibrosis.

Systemic glucocorticoids:
Hydrocortisone 25mg tablet dose of lOOmg/day is
useful in relieving in burning sensation.
Triamcenolone or 90 mg of Dexamethosone is given
supplemental with local i njection of hydrocortisone
biweekly intervals on affected side.

(c) Physiotherapy.
This includes measures such as forceful mouth
opening and heat therapy. Heat has been commonly used
and the results been described as satisfactory.

(d) Local drug delivery.
Local injections of corticosteroids and placental
extract have been tried in addition to hyaluronidase,
collagenase and similar substances which break down
intercellular cement substances and also decrease collagen
formation.


(e) Combined therapy
3,28,29
.

With peripheral vasodilators (nylidrin hydrochloride,
pentoxyfylline), vitamins D, E and ' B' complex, iodine,
placental extract, local and systemic corticosteroids and
physiotherapy claim a high success rate in OSF
management. Pentoxifylline is a tri-substituted
methylxanthine derivative. The drug pentoxifylline is said
to have the property of suppressing leukocyte function
while altering fibroblast physiology and stimulating
fibrinolysis. Its immuno- modulating actions include
increasing leucocyte adhesion. It also causes neutrophil
degranulation and the release of peroxides, promotes
natural killer cell activity and the production of tumor
necrosis factor, and inhibits T and B cell activation

The evaluation of the merits and disadvantages of
individual items in treatment is not possible due to the use
of combined treatment protocols; unavoidable at present
because of the empirical nature of each approach.

(f) Surgical management
20,28

Khanna JN and Andrade NN (1995) developed a
group of classification system for the surgical management
of OSF based on clinical and histopathological features. It
consists of
Group I: Very early cases
Group II: Early cases
Group III: Moderately advanced cases
Group IV A: Advanced cases

Group IV B: Advanced cases with pre-malignant
and malignant changes.

Measures such as forcing the mouth open and cutting
the fibrotic bands have resulted in more fibrosis and
disability. Sub mucosal resection of fibrotic bands and
replacement with a partial thickness skin or mucosal graft
has also been attempted along with procedures such as
bilateral temporalis myotomy. At a retrospective glance,
surgery seems to be a poor option in the overall
management of the disease.

g) Laser surgery
28
.
Carbon dioxide laser alleviates the functional
restriction when compared to traditional surgical technique.
Under general anesthesia carbon dioxide laser is used to
incise the buccal mucosa and vaporize the sub mucosal
connective tissue to the level of buccinator muscle.

(h) Effect of glutathione.
An increase in resistance of cells to oxidative damage
and toxic compounds may be achieved by increasing the
intracellular glutathione levels. Glutathione is present in
foods such as walnuts, avocado, and asparagan, apar t from
fresh fruits, vegetables and fish, meat.

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Oral Submucous Fibrosis

Premalignant Lesions and Conditions 33

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