OSMF

ORAL SUBMUCOUS FIBROSIS
By- Dr. Mahima Tyagi
P.G. IInd Year

Contents
• Introduction
• Definiton
• History
• classification
• Epidemiology
• Etiology
• Pathogenesis
• Clinical features
• Precancerous nature and malignant transformation
• Investigations
• Management

Introduction
• The concept of oral precancer is
especially relevant to Indian
subcontinent.
• Because of cultural habits of betel nut,
betel leaf chewing , reverse smoking.
• The assault on the oral mucosa starts
from a very young age due to highly
spicy food habits.

• Genetic structure of indians itself may
predispose to the increased incidence of
conditions like osmf?
• Oral precancer then is an intermediate
clinical state with increased cancer risk,
which can be recognized and treated,
obviously with a much better prognosis
compared to full blown malignancy.

• Oral precancerous condition is defined
as generalized alteration in state of
condition of oral mucosa associated with
significantly increased risk of malignant
transformation.
• OSMF
• Sideropenic dysphagia
• Syphlitic glossitis
• Xeroderma pigmentosum

• Oral precancerous lesions is defined as a
localized area of morphologically altered tissue
where cancer is more likely to occur than its
normal counterpart.
• Leukoplakia
• Erythroplakia
• Erosive lichen planus
• Bowen’s disease
• Dyskeratoses congenita
• DLE
• Stomatitis nicotina

Definition
• An insidious chronic disease affecting any
part of the oral cavity and sometimes
pharynx, although occasionally preceded by
and/or associated with vesicle formation. It
is always associated with juxtaepithelial
inflammatory reaction followed by
fibroelastic changes of lamina propria, with
epithelial atrophy leading to stiffness of oral
mucosa and causing trismus and inability to
eat.

History
. The condition was prevalent in the days of
Sushruta(600BC) , a great practioner of
ancient medicine where he labelled this
condition as “vidhari” . after lapse of many
years , Schwartz was the first person to
bring this condition again into limelight.he
described this conditon as ‘atrophica
idiopathic mucosae oris’. After that condition
has also been described as idiopathic
scleroderma of mouth , idiopathic palatal
fibrosis.

later in 1953, Joshi from Mumbai
redesignated the condition as osmf
implying predominantly its histological
nature. The WHO definition for an oral
precancerous condition- a generalized
pathological state of oral mucosa
associated with significantly increased
risk of cancer-accords well with
characteristics of OSF.

CLASSIFICATION
• 1. Variation in structure and appereance of
normal oral mucosa
• Leukoedema
• Fordyce’s granules
• Linea alba
• 2. non keratotic white lesions
• Habitual cheek n lip biting
• Burns of oral mucosa
• Uremic stomatitis
• Nonkeratotic white lesion caused by sp.
Infectious gents

• 3. candidiasis
• Thrush
• Other forms of oral candidiasis
• e/o candidiasis
• Chr. Mucocutaneous candidiasis
• Systemic candidiasis

• 4. keratotic white lesions with no
increased potential for oral cancer
• Stomatitis
• Traumatic keratoses
• Keratotic lesion with dental
restorations
• I/o skin grafts
• Focal epithelial hyperplasia
• Oral genodermatoses

5.Red and white lesions with defined precancerous
potential
• Leukoplakia and erythroplakia
• Oral lesions associated with ue of tobacco
• Carcinoma in situ
• Bowen’s disease
• Osmf
• Actinic chelitis
• DLE
• Dyskeratotic congenita
• Lichen planus
• Lichenoid reactions

Epidemiology
The disease is very common in India, Indian
subcontinent and other asian people. The
prevalence rate of OSMF in
India,Burma,South Africa ranges from 0 to
1.2 %.
In India overall incidence is about 0.2 % to .5 %.
The global incidence of submucous fibrosis is
estimated at 2.5 million individuals . The
prevalence in indian population is 5% for
women and 2% men.

Etiology
• Epidemiological and in vitro experimental
studies have shown that chewing areca nut
(Areca catechu) is the major aetiological
factor for OSF (Caniff and Harvey, 1981).
Although there are regional variations in the
type of areca nut products used in India, the
betel quid (BQ) was the most popular and
prevalent habit in ancient Indian culture. But
in 1980, both areca quid products such as Pan
masala (Areca quid) and Gutkha (AQ tobacco)
were introduced in Indian market as
commercial preparations. Since then there

• Increase in the use Pan Masala (Areca
quid) and Gutkha (AQ + T) in the
younger age groups, which had lead to
increased incidence of OSF (Gupta et
al., 1998). Pan Masala (Areca quid)
includes areca nut, catechu, lime,
flavours and spices. Gutkha (AQ + T)
contains all ingredients of Pan Masala
(AQ)

• plus tobacco and other contents, that
are closely guarded secretes and is a
commercial substitute to local
preparation popularly known as Kharra/
Mawa (Sinor et al., 1990). The rapidly
increasing prevalence of this habit can
be judged from the reports that the
Indian market for Pan masala is worth
25 billion (US$ 500 million) (Gupta and
Ray, 2004).

• Shaiu and Kwan in 1979 showed no relation
between chilli consumption and osmf. Seedat
and Vanwyk did not find any significant
relation between amount of chillies consumed
and OSMF developing in 71 osmf patients ,
they also reported a 103 cases of betel
chewers without this condition.

Observation from a 10 years study from
Ernakulum in india also did not favor this
agent to be etiology . Some ecological
arguments were also against chilli being the
etiological agent from Mexico and some
S.American countries the intake of chilli
equals or even exceeds that of indian
consumption and there are no reported cases
of osmf from these regions. Several
investigations have reported anemia, vitamin,
iron and protein deficiency as causative of
osmf.

Wahi et al showed high frequency of clinical
manifestation with deficiency of vitamin A,B
and C and low serum levels of the vitamins
observed in osmf patients .
Cannif et al probed into a possible genetic
susceptibility for this condition , they
performed HLA typing and observed that the
frequency of HLA-A10,DR-3 and DR-7 in the
samples of 44 patients.

the familial occurene of this condition was also
reported in India and South Africa . In an
study of 60 cases , 7 individulas were sibling
from same family.
Caniff et al reported an intresting finding that ,
there is an increase inDR-3 antigen in osmf
along with presence of serum immunoglobulin
and autoantiodies.

Eugenol , another major contituent of
betel nut quid is cytotoxic to oral
submucous fibrosis in vitro at conc
exceeding 3mMol/l where as it has
protective , effect of inhibiting the
xanthene oxidase actibvity and lipid
peroxidase at levels below this.

• Areca nut is currently considered to be
the most important etiological factor
for osmf . It is often erroneously
referred referred to as betel nut. It is
Endosperm of fruit from the areca
catechu tree. The fruit is orange yellow
in color when ripe , the fibrous pericarp
is removed from the seed or endosperm
, which is then used fresh , after sun
drying or in crude form.

Areca nut contains Tannins of which gallotannic
acid and D-catechol is important components.
It contains several alkaloids of, which
arecoline is most important and abundant.
Daftary studied 405 cases of osmf nd his
results gave a strong relation between osmf
and areca nut, where 77% patients were
using areca nut in some form or the other.

CC.W. Vanwyk and A.Oliver performed a study
in South Africa that showed that arecoline
inhibit and terminate cultured fibroblast in a
concentration gradient dependent manner.
Vander Bijl and Vaneyk performed yet another
study in south africa ,the study inferred that
r-Arecadine is basic in nature and with a pH
of 6.84 and is lipophilic, diffuses through the
mucosa with ease whereas its other form
arecadine has low flux rates when compared
to its lipophilic counterpart

but the presence of an alkaline
enviorment in oral cavity due to the
additon of lime in the quid readily
hydrolyses arecoline to arecadine, the
latter component in its predominantly
ionized form in an alkaline enviorment,
would then permeate the mucosa at a
slower rate than its
methylester.(Arecoline)

Yu chaochang from taiwan studied the
synergistic effects of nicotine on
Arecoline inducing cytotoxicity in human
buccal mucosal fibroblasts. The study
sites arecoline as the major areca nut
alkaloid and considers it the most
important etiological factor in areca
nut.

To date large number of quid chewers are
smokers , further more, nicotine is the
major content of tobacco and was added
to the study to test how it would
modulate the cytotoxicity of arecoline.
At concentrations of 50µg/ml arecoline
was cytotoxic to human buccal mucosa in
a dose dependent manner.

Systemic factors
Chronic irritation
Nutritional deficiency
Defective iron metabolism
Bacterial infections
Collagen disorders
Immunological disorders
Genetic susceptibility
Altered salivary composition

Chronic irritation
• 1.Chillies- the use of chillies have been
thought to play an etiological role in osmf.
Capsaicin is the active ingredient of chillies.
It is the vanillylamide of 8- methyl-6-noneic
acid which is the active irritant of chillies.
• 2. Tobacco- it is a known irritant and
causative factor in oral malignancy. It may act
as local irritant.

• 3.Lime- it is used with betel nut for chewing.
It causes local irritation and damage to the
mucosa with vesicle and ulcer formation in
susceptible individuals. It act as local irritant.
• 4.Betel nut- the term areca nut is used to
denote the unhusked whole fruit of areca nut
tree and term betel nut is used exclusively to
refer to inner kernel or seed which is
obtained after removing husk.

• Quid has been defined as a substance or
mixture of substances placed in the mouth or
chewed aingredients tobacco and/or areca nut
in raw or any manufactured or processed form
(Zain et al., 1999). The major areca nut
alkaloids are arecoline, arecadine, arecolidine,
guyacoline and guacine (IARC anonymous,
1985). The important flavonoid components in
areca nut are tannins and catechins. These
alkaloids undergo nitrosation and give rise to
N-nitrosamine which might have cytotoxic
effect on cells (Hoffmann et al., 1994).

• The betel quid is placed in the buccal
vestibule for about 15 minutes to an hour and
repeated 5 to 6 times a day which leads to
constant contact between the mixture and
oral mucosa. The alkaloids from the quid are
absorbed into the mucosa and undergoes
metabolism. Microtrauma produced by the
friction of coarse fibers of areca nut also
facilitates diffusion of the alkaloids into the
subepithelial connective tissue resulting in
juxtaepitheial inflammatory cell infiltration
(Chiang et al., 2002)

• Oral submucous fibrosis (OSF) is widely
considered to be a potent precancerous
condition whose predominant
characteristics are the excessive and
abnormal deposition of extracellular
matrix (ECM) components that may
affect adversely the routine oral
functions. Increasingly, it has become
appreciated that certain of these
actions of ECM derive from its ability
to sequester and modulate the activity
of specific growth factors (Nathan and

• Of all of the growth factors, none has been
found to have the diversity of effects on
ECM ascribed to transforming growth factor-
(TGF-). This peptide plays a critical role not
only in synthesis and degradation of ECM but
also in response of cells to ECM mediated
through integrin receptors.

Pathogenesis
• A previous theory stating that a
common inability to tolerate food
seasoned with chillies (capsicum annum/
C.fructscene) in patients with OSF lead
to the hypothesis being that the
disease was due to some form of
hypersentivity to capsaicin the irritant
in chillies

• Sirsat et al subjected the palate of rats
to painting with capsaicin this only
produced a limited connective tissue
response unless the animals were
depleted of vitamin B- complex. Another
objection was that there are no
reported cases of osmf in patients from
mexico, where the consumption of
chillies equals or even exceeds that of
Indian population.

• Peterson and Kelly in 1919 independently
discussed the symptoms of chronic
dysphagia and the atrophy of the
mucosa of the upper git in middle aged
women, who are chronically anemic,
further more Waldenstorm and
Kjillberg showed the significant diminish
of iron stores and stainable iron in the
bone marrow.

Reenie et al showed that in human iron
deficiency anemia and experimental iron
deficiency anemia in hamsters ,
quantitative histological changes in the
oral epithelium are demonstrable. The
epithelium is atrophic with a reduced
maturation compartment but an
increased cell kinetic has shown an
increased cell production , indicating
despite atrophy epithelial tumors are

The epithelium is atrophic with a reduced
maturation compartment but an increased
keratinized compartment, cell kinetics has
shown an increased cell production,
indicating that, despite the atrophy, the
epithelial tumors are rapid.
An animal study showed that they were more
susceptible to oral cancer if they were
deficient in iron, than normal rats when,
there was a carcinogens used on them.

Although most of the interest is shown in
the role of iron, other nutritional factors
may also be involved in the pathogenesis
of OSMF. Deficiency in folic acid ,
pyridoxine and vit B12 may be secondary
to that of iron and difficult to estimate.
Studies from India showed that 76.2% of
patients with oral and oro pharyngeal
cancers have low levels of vitamin A.

Interest has also been focussed on
chronic infections of the oral cavity and
their role in pathogenesis of premalignant
lesions and cancer development. Prominent
one, being oral candidiasis clinically and
experimentally candidiasis has been
associated with speckled leukoplakia and
OSMF. A conclusion of candidiasis and its
role in pathogenesis of OSMF is still
inconclusive however, further studies
need to be focussed on this aspect.

• Herpes simplex virus has long been
associated with cancers. HSV-1 is
associated with lip and oral cancers and
HSV-2 with uterine cervix cancers. A
definitive relation between these
viruses and development of OSMF is
still to be established, although the
viruses are closely associated with
premalignant conditions , where there
existence is proved beyond doubt.

• In many autoimmune disorders, genetic
factors play a role in the pathogenesis ,
causing abnormalities in their immune
system . Immune response genes, may
be linked to HLA-DR locus of the major
histo compatibility complex in humans
and association between this locus and
autoimmune disease has been sought.

• Khadim reported that additon of
tobacco to the betel quid , increases
the risk from 4(without tobacco), in the
quid to as much as 29(with tobacco) in
the quid.

• Ma R.H. et al (1995) in their in vitro
study of OSMF, concluded that
deposition of large amount of collagen
fibers in OSMF tissue could be
considered to be associated with
increased lysyl oxidase activity and it is
implied that the OSMF fibroblasts
secrete abnormal amounts of lysyl
oxidase in certain processess during
collagen synthesis.

• TrivedyC. Et al(1999) in their studies
observed that copper level was
increased in patient with osmf. Areca
nut has been shown to have high copper
content (302nmol/g) compared with
other conventional nuts (22- 173nmol/g)
and chewing areca nut 5-30 min
significantly increases soluble copper in
whole saliva mouth fluid.

Interlukin-6(IL-6)
• The effects of these cytokines,
especially IL-6 may in turn be
dependent on the intracellular
glutathione levels; depletion of which
also promotes fibrosis. COX-2
expression has also shown to be
amplified in OSMF.

• It is shown tht normal buccal mucosal
fibroblasts express very low levels of
COX-2 immunohistochemical expression
as compared to OSMF FB , suggesting
that arecoline causes persistent tissue
inflammation which can precipitate
fibrosis.

• Any external factor , which causes any
form of injury to tissue , can elicit a
protective inflammatory process. Over a
period of time , due to persistent habit,
chronic inflammation sets in at the site.
Initial irritation leads to further
atrophy and ulceration of the mucosa .
It has been found that alkaloid
exposure of buccal mucosal fibroblasts
result in accumulation of collagen.

• A decreased degradation of collagen
due to increased cross-linking of the
fibers and reduced collegenase activity
are found in OSMF mucosa compared to
normal oral mucosa. This evidence
implies that OSMF may be considered a
collagen metabolic disorder resulting
from exposure to areca nuts.

TGF-β
• Collagen is the major structural
component of the connective tissues and
its composition with in each tissue
needs to be maintained for proper
tissue integrity. The synthesis of
collagens is influenced by a variety of
mediators, including growth factors,
hormones, cytokines and lymphokines.

• About 27 types of collegen have been
recognized, which can be grouped into 7
broad classes. Major class is fibrillar
collagen, among them types I,III,and VI
form a major part of connective tissue.
A prominent mediator is TGF-β, TGF-β1,
in particular, seems to be one that plays
major role in wound repair and fibrosis.

• This growth factor has also been
implicated in the development of many
fibrotic diseases. It causes deposition
of ECM by synthesis of matrix proteins
like collagen and decreasing its
degradation by stimulating various
inhibitory mechanisms.

• Although TGF-β is essential for healing,
overproduction leads to scar tissue, and
fibrosis. As in other fibrotic disease, TGF-
β signalling pathway might be critical for
pathogenesis of OSMF. The molecular
events are discussed in 2 main sections
regulated by TGF-β and flavonoids present
in areca nut:
• Collagen production pathway and
• Collagen degradation pathway.

Collagen production pathway
• There are 3 main events in this pathway
activation of procollagen, elevation of
procollagen proteinase levels and
upregulation of lysyl oxidase.
• Collagen is the most abundant protein in
human body and plays an important role in
the structural element of connective
tissue. They are triple helix stablized by
unusual crosslink.

• Procollagen genes are transcribed and
translated to form procollagen monomeric
chains. The genes
• COL1A2
• COL3A1
• COL6A1
• COL6A3
• COL7A1 have been identified as definitive
TGF-β targets.

• Activation of procollagen genes by TGF-
β cause an increased expression of
procollagen genes and hence increases
collegen level in OSF.
• Elevation of procollagen proteinase such
as PCP tnat cleaves C-terminal and PNP
that cleaves N- terminal play essential
role in pathogenesis of OSF.

Up regulation of LOX
• The enzyme lysyl oxidase is found to be
upregulated in OSF (Trivedy et al., 1999).
This is a copper dependent enzyme (Kagen and
Trackenman, 1991) and plays a key role in
collagen synthesis and its cross linkage. The
possible role of copper as a mediator of
fibrosis is supported by the demonstration of
up regulation of this enzyme in OSF biopsies
(Trivedy et al., 1999) and in OSF fibroblasts
compared to normal fibroblasts grown in
culture (Ma et al., 1995).

Collagen degradation pathway
There are two main events modulated by
TGF which decreases the collagen
degradation
Activation of inhibitor of MMP gene
TIMPs
Activation of plasminogen activator
inhibitor PAI gene.

• TGF-β activates the genes for TIMPs ;
thereby more TIMP is formed. This
inhibits the activated collegenase
enzyme that is necessary for
degradation of collagen. It also
activates the gene for PAI , which is
plasminogen activator, thus there is no
plasmin formation. Plasmin is required
for conversion of procollegenase to
active form of collegenase and absence
of plasmin results in absence of active
collagenase.

• The flavonoids inhibit the collegenase
activity . A reduction in the activity and
levels of collegenase results in decrease
in collagen degradation.

TGF-β-
transforming
growth factor –
beta
PAI- plasminogen
activator inhibitor
TIMP- tissue
inhibitor of matrix
metalloproteinase

Role of copper in OSMF
• High levels of copper in areca nuts ,
major etiological factor in OSMF plays
an initiating role in stimulation of
fibrinogenesis by up regulation of lysyl
oxidase and thereby causing inhibition
of degradation of collagen and causing
its accumulation thereby causing OSMF.

• Margalith et al suggested that role of
copper ions in biological damage is
caused by superoxide radicals or other
reducung agents such as ascorbate,
which reduce the copper complex. These
complexes react with H2O2 to form
hydroxyl radicals that cause damage to
protein RNA and DNA that are not
repairable by cellular mechanisms thus
initiating the malignant process.

Role of iron in OSMF
• Serum iron levels are considered as
biochemical indicators for nutritional
assessment. Utilization of iron in
collagen synthesis by the hydroxylation
of proline and lysine leads to decreased
serum iron levels in OSMF patients. In
most cases clinical anemia may be
contributing factor (Ramanathan et al)

• Ramanathan put forward a study in Malaysia
and hypothesized that it was the asian version
of Sideropenic Dysphagia where chronic iron
deficiency leads to mucosal susceptibility to
chili and areca nut. He observed iron
deficiency anemia in 10 out of 13 patients.
Some of these studies were supported by
case controlled studies.

Role of heat shock protein
• HSP47 is a 47kDa collagen binding HSP
which belongs to serine protease
inhibitor .
• HSP47 is k/a molecular chaperone that
is specifically involved in processing and
quality control of collagen molecules.
• Shung et al (2008) first found that
arecoline is capable of stimulating
HSP47 mRNA expression in buccal
mucosal fibroblasts.

Referrences
• Shafer- a textbook of pathology . 5th edition
• Rajendran rR. Osmf- etology, apthogenesis and
future reearch. Bulletin of WHO .1994.
• Cannif . OSMF – pathogenesis and management.
British Dental Journal. 1986:160
• OSMF- review on etiopathogensis- Journal of cancer
science & therapy.
• Fundamentals of oral medicine and radiology-
Durgesh N Bailoor

CONTENTS
• CLINICAL PRESENTATION
• STAGING
• PATHOLOGY
• MALIGNANT TRANSFORMATION
• REFERRENCES

CLINICAL PRESENTATION
1.TRISMUS-restriction in mouth opening
2.BURNING SENSATION-especially to
hot and spicy food.
3.NASAL SPEECH-in several cases
4.BLANCHED & FIBROTIC MUCOSA –can
involve all the mucosa, tongue, floor of
mouth ,the vestibular and faucial pillars.
5.BUD LIKE UVULA

• Blanching
• Localized blanching is caused by the
impairment of the local vascularity (
narrowing of blood vessels ). The
disease often starts as a blanched area
and palpable fibrous bands develop over
a period of time . Blanching may be
localized diffused or reticular.

• Diffuse blanching is when a greater part
of oral mucosa is involved. Blanching may
be asymptomatic or accompanied by
burning sensation of the oral mucosa
and salivary changes. Reticular blanching
consists of blanched areas, with
intervening clinically normal mucosa ,
giving it a lace like appereance . Over a
period of time, one type of blanching
may change into another type.

• Vesicles
• Vesicles are usually reported and noted
on history basis and documented in 32%
of the cases. These vesicles are small
and subepithelial. They rupture early
because of masticatory trauma , after
the intake of hot or spicy food,
suggesting an allergic response, as the
primary pathogenesis mechanism in
OSMF.

• Ulcerations
• Ulceration is more marked in advanced
cases and are reported in 43% of these
cases. Initial irritation leads to further
atrophy and ulceration of the mucosa.
Moreover, there is nutritional deficiency
which leads to loss of integrity of
epithelium. Petechiae were observed in
22% of the cases. They may be few or
many, occuring most commonly on the
tongue, the labial and buccal mucosa.

• Salivary glands
• 93% of saliva is secreted by major
salivary glands and only 7% of saliva is
secreted from minor salivary glands.
There is no scientific data that sheds
light on the effect of osmf on major or
minor human salivary glands.

• The mechanism of xerostomia in osmf
patients is still not clear, but may be
due to fibrosis in the oral mucosa which
partially or completely obliterates the
major and minor salivary gland ducts
resulting in decrease in saliva secretion
and a possible acinar cell atrophy of the
salivary gland involvement.

• Nyachhyon R et al (2011) observed
degeneration of the acini in the form of
loss of cellular and acinar outline,
changes in the nucleus and mucin
pooling.

• Hearing sensation
• Mild hearing loss due to blockage of
eustachian tube which opens in
nasopharynx. It happens in patients who
used to swallow the quid. Dysphagia is
also seen in such patients due to
fibrotic changes in pharynx. Mild
gustatory loss is also reported due to
depappillation of tongue and loss of
taste buds on dorsum of tongue.

Staging of OSMF
• 1.Gupta Dinesh Chandra from Nagpur
put forward the grading depending on
the clinical conditions as:
• GRADE I: only blanching of oral mucosa
without symptoms
• GRADE II: burning sensation, dryness
of mouth, vesicles, ulcers in mouth
without tongue involvement.

• GRADE III: in addition to grade II
restriction of mouth opening.
• GRADE IV : In addition to grade III
palpable bands all over the mouth
without tongue involvement.
• GRADE V:grade IV + tongue also
involved.
• GRADE VI:osmf along with
histopathologically proven oral cancer.

• 2. Haider & a.t. Merchant put forward
the clinical and functional staging as:
• CLINICAL STAGING:
• a) faucial bands only
• b) faucial and buccal bands.
• c) faucial, buccal and labial bands.

• FUNCTIONAL STAGING
Mouth opening≥ 20mm
mouth opening 11-19mm
mouth opening ≤ 10mm

• 3. Khanna and Andrade in 1995
developed a group classification system
for the surgical management of trismus
• Group I: earliest stage without mouth
opening limitations with an interincisal
distance of >35mm.
• Group II : patients with an interincisal
distance of 26-35mm.

• Group III :moderately advanced cases
with an interincisal distance of 15-
26mm. Fibrotic bands are visible at the
soft palate , and pterygomandibular
raphae and anterior pillars of fauces are
present.
• Group IVA: severe trismus, interincisal
distance of 15>mm and extensive
fibrosis of all the oral mucosa.

• Group IV B: disease is most advanced ,
with premalignant and malignant changes
throughout the mucosa.

PATHOLOGY
• Structural and microstructural changes
• an evaluation of the epithelial changes in
different grades of OSMF shows that
increase in clinical severity of the
disease may be accompanied by
epithelial hyperplasia or atrophy , which
is associated with an increased
tendency for keratinizing metaplasia.

• The epithelial atrophy reported by
Pindborg and associates is one of the
marked changes in OSMF, which
contrasts with the predominantly
hyperplastic epithelium reported by
Sirsat & Khanolkar and by Wahi and
associates.
• Wahi et al correlated type of
keratinizing metaplasia with site of
lesion and habits of the patients.

• It is generally agreed that site of lesion
and habits of the patients. It is
generally agreed that the pathologic
alteration in OSMF begins in the lamina
propria and the epithelium responds
secondarily to it . A persistent
juxtaepithelial inflammatory response is
characteristically seen in OSMF.

• The hyperplastic epithelial response,
noticed during the early and moderately
advanced stages of OSMF, may be a
reaction to this.
• An alternative explanation for the
epithelial hyperplasia is an adaptive
response to local irritants to provide a
greater degree of protection to
underlying tissues.

• Subepithelial changes:
• On the basis of the histopathological
appereances of stained (H& E) sections,
the surgical specimens from OSMF can be
grouped into 4 definable stages:
• Very early
• Early
• Moderately advanced
• advanced

• These stages are based not only on the
amounts and nature of the subepithelial
collagen, but also on the following criteria
taken together:
• Presence or absence of oedema
• Physical state of mucosal collagen
• Overall fibroblastic response
• State of the blood vessels
• Predominant cell type in the inflammatory
exudate

• Persistent dilatation has also been seen
in many moderately advanced and
advanced biopsies . Blood vessels usually
undergo dilatation to compensate for
hypoxia , resulting in ruptured blood
vessels and scattering of RBC’s in the
connective tissue stroma.

• The presence together of large no of
lymphocytes and fibroblasts , as well as
plasma cells in moderate numbers,
suggests the importance of a sustained
lymphocytic infiltration in the
maintenance of the tissue reaction in
OSMF . Using standard connective
tissue staining methods, Hammer et al.
demonstrated abnormal juxta epithelial
connective tissue, indicating a probable
alteration in the collagen.

Malignant transformation
• The precancerous nature of OSF was
first described by Paymaster in 1956
when he observed slow growing
squamous cell carcinoma (SCC) in one
third of the patients with the disease.
This was confirmed by various groups
and Pindborg in 1972 put forward five
criteria to prove that the disease is
precancerous (Pindborg et al., 1984).

• They included, high occurrence of OSF
in oral cancer patients, higher incidence
of SCC in patients with OSF,
histological diagnosis of cancer without
any clinical suspicion in OSF, high
frequency of epithelial dysplasia and
higher prevalence of leukoplakia among
OSF cases (Pindborg et al., 1967).
Malignant transformation rate of OSF
was found to be in the range of 7–13%.

According to long term follow-up studies a
transformation rate of 7.6% over a period
of 17 years was reported (Murti et al.,
1985).
Authors hypothesize that dense fibrosis
and less vascularity of the corium, in the
presence of an altered cytokine activity
creates a unique environment for
carcinogens from both tobacco and areca

• Less vascularity may deny the quick
absorption of carcinogens into the
systemic circulation (Tilakaratne et al.,
2006). An observation which is still
intriguing in the pathogenesis of OSF
and its subsequent malignant
transformation is the often reported
cases of carcinomas, rather than
sarcomas associated with the disease

• The pathogenesis for malignant
transformation is not precisely known
and is thought to be multifactorial. The
cariogenecity of tobacco in synergism
with areca nut is well known, but
recently the cariogenecity of areca nut
alone without tobacco has also been
identified by Jeng et al.

• Its genotoxic and mutagenic effects
have been attributed to its content of
polyphenols and alkaloids as well as
presence of areca nut specific
nitrosamines like N-nitrosoguvacoline,
N-nitrosoguvacine , 3-propionaldehyde,
and 3-propionitrile. Moreover, the
increased levels of reactive oxygen
species in areca nut enhanced by the
presence of slaked lime in the quid

• have also been implicated in oxidative
DNA damage. The nutritional deficiency
, consistent immunologic abnormalities ,
altered cytokine levels , mechanical
trauma , increased age , presence of
other habits ( tobacco and alcohol) , and
genetic vulnerability observed in OSMF
further increase risk for malignant
transformation in OSMF.

• Additional factors include presence of
epithelial atrophy which may allow
enhanced permeability of the
carcinogens and the reduced vascularity
in the lamina propria may prevent quick
absorption of carcinogens into systemic
circulation , resulting in exposure to
carcinogens for a longer duration.

REFERRENCES
• Nyachhyon R1,et al. minor salivary gland
changes in osmf.journal of nepal dental
association vol 12,no1, jan-jun26-28.
• Textbook of Oral Medicine-
Dr.Ravikiran Ongole
• Burkets Oral medicine-11the edition
• Deepa Das et al. JIAOMR,2010
• Disease of tropics by S.R. Prabhu

MANAGEMENT
• Behavioural therapy
• Pharmacological therapy
• Topical therapy
• Intralesional therapy
• Systemic therapy
• Physiotherapy
• Surgical therapy

Behavioural therapy
• Strict discontinuation of chewing habits
of areca nut & betel leaf.
• Protein rich diet, calcium, iron and
vitamin rich diet should be taken.
• Should have bland food, free from
chillies and peppers.

Pharmacological therapies
• Topical application therapy
• Intralesional injections
• Systemic therapy

Topical application therapy
• Topical steroids
• Hyaluronidase
• Turmeric
• Urea-Papain mixture
• Acetic acid

Steroids
• Supresses immune system
• Decreases inflammation
• Therapeutic effects
• Antiinflammatory & have direct
healing action.
• Relieves ulceration & painful mucosa.

Topical steroid application
• Dexamethasone with or without
hyaluronidase, locally has been reported
with good results.
• Hyaluronidase alone- better results
over the short term.
• Hyaluronidase + dexamethasone- better
long term results.

• Nowadays 0.12% betamethasone
velerate ointment.
• Betamethasone (betensol) 0.5 mg
mouthwash is given to relieve pain and
burning sensation. Though these
preparations are effective, the
presence of saliva can dilute the drug
and decrease effectiveness.

• Or they can be combined with orabase
for longer stay against oral mucosa. But
the amount of drug released into lesion
is considerably reduced.

• Steroid mucous patches:
• Dr. Sumanath KN and Dr. Ravikiran
Ongole(2010) studied the efficacy of
dexamethasone mucosal patch for
OSMF. Study was done in 10 patients
(intralesional vs mucous patches).
• These were more effective than
intralesional injection but caused
discomfort to patient.

• Turmeric
• Turmeric and its active ingredient
“circumin” is considered to be
chemopreventive agents. Turmeric and
its essential oils have anti
inflammatory, antioxidant and anti
cancer property.
• Circumin and turmeric oil have been
reported to reduce burning sensation in
pre cancer.

• Turmeric has been described as a dual
inhibitor of arachidonic acid
metabolism, as it inhibits both
cyclooxygenase and lipoxygenase
pathway for inflammation, thus
inhibiting the products of inflammation
such as prostaglandins, leukotrines.

• Rao et al described scavenging action of
the circumin on superoxide radicals,
hydroxyl radicals and lipid peroxidation.
• In chinese medicine circumin & turmeric
are regarded as having fibrinolytic
effect on liver and lung fibrosis by
Kuttan et al.

• Kerry bone reported that circumin
alters metabolism of carcinogens in liver
and increases the activity of carcinogen
detoxifying enzyme glutathione-s-
transferase, thus preventing
carcinogenesis. The choice of therapy is
always beneficial, affordable and non-
invasive in OSMF.

• Urea-papain mixture-applied intraorally
2-3 times for 15days.
• 100gms- urea
• 100gms papain
• 100gms glycerine
• 10gm sodium carboxymethicellulose
• 2gm vaniline
• 1000cc distilled water

• Papain is biogenic stimulator and has
proteolytic action. Urea is keratinolytic
and its early absorption causes
breakdown of fibropeptide linkages of
fibrous layer leading to decrease in
stiffness improved laxity of mucosa.

• Acetic acid
• Dr. R.Rajendran put forward a new
treatment approach for managing osmf
which is cost and performance efficient.
A study was done on 45 patients of
either sex and age ranging from 32-60
years suffering from osmf, having a
mean mouth opening ( 2.83 cms)
comprising study group.

• All patients were randomized into 4
groups:
I. 4% acetic acid group (15)
II. Multivitamin group (10)
III.Hot water exercise group(10)
IV.10 patients were used as controls without
any treatment.

• Results- significant increase in mouth
opening was found with 4% acetic acid.
This is due to when dilute acid comes in
contact with collagen it causes collagen
to swell up and thus breakdown of
collagen crosslinkage causing partial
degeneration, which further progress to
and collagenolysis.

• Intralesional injections:
Inj. Hydrocortisone
Inj. Hyaluronidase
Inj. Placentrax
Chymotrypsin
Interferon Ÿ
Combinations

• Hydrocortisone
Inj .hydrocortisone contains
• Hydrocortisone acetate
• Benzyl alcohol
• Carboxymethyl cellulose

• It suppresses edema ,
• fibrin deposition,
• capillary exudation,
• migration of phagocytes in inflamed
area.
• Also suppresses capillary proliferation,
fibroblastic proliferation
• Deposition of collagen and
• antiinflammatory

• Hyaluronidase
• Injection hyalase contains hyaluronidase
(1500 IU in 1ml). It is a soluble protein
enzyme product and has specific action
on hyaluronic acid which is found in the
ground substance in the connective
tissue and act as barrier to fluid
diffusion.

• It breaks down the hyaluronic acid,
hence lowers the viscosity of
intracellular cemental substance. It
reduces formation of collagen and
facilitates penetration of other drugs.

• Placental extract
Essential biogenic stimulator.
• nucleotides- RNA and ATP
• Enzymes-alkaline acid phosphatase
• Glutamic acid and pyurvic acid
• Vitamins- vitaminE, B,B6,B12,pantothenic
acid, nicotinic acid, biotin, and folic acid.
• Steroids-17, ketosteroid
• Fatty acids- linoleic acid, lenolenic acid,
palmitic acid
• Trace elements- Cu,Se,Mg

It can be of 4 types:
• Aqueous extract
• Lipid extract
• Immune gabba globulin
• Tissue coagulated

Only aqueous phase acts as biogenic
stimulator.
Accelerates cellular metabolism
Aids in absorption of exudate
Stimulates regenerative process
Increases physiological function of
organs
Enhancement of wound healing
Antiinflammatory effect

• Ramanjaneyalu and Prabhakar Rao
advocated 2cc of placentrax injection
intralesionally at weekly intervals for 10
weeks. They have found it was superior
to cortisone. Two cortisone resistant
cases also responded well to placentrax.

• Combintions
• Sinha and Jain (1978) have tried local
injection of hydrocortisone 1.5cc for
one group and 2cc of placentrex , once a
week for other group for 1 consequent
weeks. The reported failure rate of
7.2% for hydrocortisone and 31.3% for
placentrax concluding that the
hydrocortisone was superior.

• Kakhar and Puri et al(1985) recommended
4 different regimes.
• 1st- 4mg dexamethasone biweekly
• 2nd-1500IU of hyaluronidase with 1 cc
lignocaine biweekly
• 3rd-4 mg dexamethasone and 1500 IU of
hyaluronidase
• 4th -2 cc of placental extracts biweekly.
3rd regimen for 7 weeks if proceeded by 3
weeks hyaluronidase can give maximum
benefit.

• Interferon gamma
• M.F.Haque (2001) put forward the
management modality for osmf. They
introduced concept of interferon
Ÿ,which is known as antifibrotic
cytokine. They studied 29osmf patients
18 women and 11 men with intralesional
recombinant interferon Ÿ.

• The intralesional injections were given
twice a week for 8 weeks giving total of
15 injections.
• The mechanism of action being that
INFŸ has a down regulatory effect on
cell population proliferation and collagen
production in fibroblasts taken from
patients with hypertrophic scars.

• At molecular level INFŸ upregulates the
expression of MHC classII antigen
presenting cells and vascular
endothelium to increase the synthesis
of collegenase. Injections of INFŸ
produced a few side effects
experienced by patients they were
simple headache flu like symptoms and
myalgia.

• Advantage
• High saturation of the drug is achieved .
Reduces the systemic effects.
• Disadvantages
• It requires multiple injections which causes
unneccessary trauma to the already inflamed
area.
• It is very painful.
• More discomfort to the patient
• The painful treatment procedure may
discourage the patient to seek treatment.

Systemic therapies
1.Micronutrients and vitamins
2. Levamisole
3.Pentoxiphyllin
4.Immune milk

• Vitamin A
• Antioxidant. Essential for the
• maintainence of structural integrity & role
in
• induction &control of differentiation of
epithelium and
• inhibition of keratinization.
• Deficiency will lead to metaplasia &
hyperkeratosis and enhance susceptibility
to carcinogensis.

• Vitamin E
• Gupta S et al (2004) reported n their
study that decrease in beta –carotene
and vit E was more significant in osmf .
After 6 weeks of oral administration of
beta carotene , and vit E, patients
showed increase in plasma level of these
2 antioxidants along with decrease in
Malonialdehyde level associated with
clinical improvement.

Vitamin C
Cystolic chain breaking antioxidant .
Reduces vitamin E degradation and
reverses cell to normal type.
Selenium
Integral part of enzyme system
’glutathione peroxidase’. Protects
intracellular structure against the
oxidative effects of free radicals.

• Zinc
• Has astringent , corrosive and weak
antiseptic properties which are
essential to protect mucosa, as a
membrane stablizer. This treatment
modality is well accepted by patients –
economically cheap, easy to take and
ultimately multivitamin therapy.

• Lycopene
• Carotenoids are natural pigments
synthesized by plants and are
responsible for the color in fruits and
vegetables. lycopene is the carotenoid
that gives tomato its bright red color.
It accounts for 50% of the carotenoids
in human serum. It has anti-carcinogenic
and antioxidant properties .

• In osmf:
• Lycopene inhibits the human fibroblast
activity
• It upregulates the lymphocyte
resistance to stress and supresses the
inflammatory response.
• It can reduce burning sensation
associated with osmf effectively.

• Steroids
• Hydrocortisone 25mg tablet in doses of
100mg/day is useful in relieving burning
sensation without any side effects.
Triamcinolone or 90 mg dexamethasone
can be given. It acts as an anti-
inflammatory.

• Pentoxiphylline
• It is a tri-substituted methylxanthine
derivative
• It increases leukocyte deformability
• Inhibits neutrophil adhesion
• Inhibit T-cell and B-cell activation
• Decreases production of TNF and IL-2

• Levamisole
• Dr.Balaji Rao used immunomodulatory
drugs .
• Used 150mg of levamisole fo 4 days
along with aquasol capsule OD for month
and than biweekly for month.
• Symptomatic relief was seen

• Penicillamine
• Lysil oxidase is a key enzyme .
• Inhibiting activity of LOX by using
copper chelator like peicillamine reduce
the fibrosis by decreasing cross linkage

• Immune milk
• Immune milk powder contains small
amount of micronutrients , it does
contain moderate amount of vitamin A,C,
B12,B2,B6, B12, iron, copper, zinc which
show improvement in signs &symptoms
of osmf patient.

• Phyto composition
• Elletaria cardomum, cinamomum
camphora, occimum sanctum, mentha
arvenis and curcuma longa
• Given as suspensions, spray, oil,
mouthwash, paste, chewing gum, gel
lotion, tablet, candy
• No side effects, highly effective, long
lasting and permanent cure for osmf.

• Physiotherapy
• Mouth opening exercises
• Heat therapies
• Local heat therapies
• Short wave diathermy
• Microwave diathermy

• Ultrasound
• Therapeutic US
• Study done on 30 patients showed
considerable improvement in mouth
opening
• Thus US can be used as alternate
palliative therapy

• Surgery
• Resection of fibrous bands without placing
any graft
• Resection with split thickness skin graft
• Resection with lateral tongue flap
• Resection with fresh human placental graft
• Resection with nasolabial flap as graft
• Resection with palatal island flap
• Resection with pedicled buccal fat pad as
graft

• Lasers
• Cryosurgery
• Green tea

• According to stages
• A.Stage I and stage II patients:
cessation of habit+ nutritional support+
intralesional steroids
• Stage III:A + IL (steroids
+hyalase/placentrex) +physiotherapy
• Stage IV :A+ Systemic steroids
+surgical therapy

• Role of US and jaw opening exercises n
cases of OSMF (IJPOT2010)
• JIDA 1980;52, 375-378
• JIDA 1998;69:226-230
• Durgesh N Bailoor-Fundamentals of oral
medicine & radiology

Action of placentrax
Placentrex is an aqueous extract of
human placenta that contains nucleotides,
enzymes, vitamins, amino acids, and
steroids. Its action is essentially
“biogenic stimulation” which suggested
that it stimulates the pituitary and the
adrenal cortex, and regulates the
metabolism of tissues. It also increases
the vascularity of tissues. Its use is
based on the method of “tissue therapy”
which explains that animal and vegetable
tissues,

• when severed from the parent body and
exposed to
conditions unfavourable but not mortal to
their existence, undergo biological
readjustment leading to development of
substances in state of their survival to
ensure their vitality. Such tissues or their
extracts, implanted or injected into the
body after resistances to pathogenic
factors, stimulate the metabolic or
regenerative processes, thereby favouring
recovery.

Action of corticosteroids.
• Inflammatory response
• This includes reduction of-
• increased capillarity permeability, local
exudation, cellular infiltration,
phagocytic activity and late responses
like capillary proliferation, collagen
deposition, fibroelastic activity and
ultimately scar formation.

• Corticoids are only palliative, do not
remove the cause of inflammmation, i.e.
underlyimg disease continue to progress
while manifestations are dampened.
They favor spread of infection as
capacity of defensive cell to kill
microorganisms is impaired.

• Imunosuppressant action
• Negative regulation of genes for cytokines
in macrophages, endothelial cells and
lymphocytes.
• Thus causing production of interlukins,
TNFæ,GM-CSF
• Fibroblast poliferation and T lymphocyte
function are suppressed, chemotaxis
interfered.

Hyaluronidase
• Hyaluronidase stimulates hydrolysis of
hyaluronic acid, which offers
resistance to diffusion of liquids
through tissues.
• Aid in absorption & dispersion of
injected drugs.

levamisole
• It is an immunomodulator – restores
depressed Tcell function. It has been
used as a disease modifying drug in
rheumatoid arthritis and as an adjunct
in malignancies.

Referrences
EFFIACY OF BETAMETHASONE, PLACENTAL EXTRACT AND
HYALURONIDASE IN THE TREATMENT OF OSMF: A
COMPARATIVE STUDY
E journal of dentistry
Efficacy of
hydrocortisoneacetate/hyaluronidase vs
triamcinolone acetonide/hyaluronidase in
the treatment of oral submucous
fibrosis
Indian J Med Res 131, May 2010, pp 665-669
K.D.Tripathi 5th edition

OSMF

Recommended

Recommended

More Related Content

Similar to OSMF

Similar to OSMF (20)

Recently uploaded

Recently uploaded (20)

OSMF