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Oral mucous membrane is a unique area of the body, which
is continuously exposed to various kinds of stresses such as
heat, cold, microorganisms, chemicals and mechanical
In response to these stresses, both epithelium and
connective tissue layers of the oral mucosa exhibit acute and
chronic reactive changes.
One such reaction of the collagen of oral mucosa to arecanut
is oral submucous fibrosis.
Oral Submucous Fibrosis (OSMF) is a chronic disease of
insidious onset and a prevailing potentially malignant disorder
characterized by juxta-epithelial inflammatory reaction along
with mucosal fibrosis.
OSMF is characterized by deposition of dense collagen in the
First described by Schwartz “atrophica idiopathic mucosae
oris” in 1952 among 5 Indian females in Kenya.
1953- Joshi from Bombay redesignated the condition as
Most widely accepted definition by Pindborg JJ & Sirsat S.M (1966)
“OSMF is an insidious chronic disease affecting any part of the oral
cavity and sometimes the pharynx. Although, occasionally
preceeded by and/or associated with vesicle formation, it is always
associated with juxta epithelial inflammatory reaction, followed by a
fibroelastic change of the lamina propria, with epithelial atrophy
leading to stiffness of the oral mucosa and causing trismus and
inability to eat”.
Oral submucous fibrosis (OSF), first described in the early 1950s, is
a potentially malignant disease predominantly seen in people of Asian
The disease is predominantly seen in India, Bangladesh, Sri Lanka,
Pakistan, Taiwan, Southern China, Polynesia and Micronesia. Several
case-series are reported among Asian immigrants to the UK and
South and East Africa. A significant variation in the prevalence of OSF
in different countries has been reported.
Pindborg (1980) quotes it as almost exclusively occurring among
Indians, Pakistanis and Burmese.
The condition was first described in ancient Indian Manuscripts
by Sushruta describing it as “VEDARI” where he describes
patients suffering from narrowing of mouth, burning sensation
The prevalence of this condition in Indian subcontinent is a
reflection of their food, cultural or religious habits.
More prevalent among younger individual (15-35 years)
AUTHORS YEAR NOMENCLATURE GIVEN
Schwartz 1952 Atrophia Idiopathica mucosa oris
Joshi 1953 Submucosa fibrosis of palate and pillars
Lal 1953 Diffuse oral submucous fibrosis
Su 1954 Idiopathic scleroderma of mouth
De sa 1957 Submucous fibrosis of palate and check
George 1958 Submucous fibrosis of palate and mucosa
Pindborg& Sirsat 1964 Oral submucous fibrosis
Goleria 1970 Sub-epithelial fibrosis
Based on clinical findings
Pindborg JJ 1989
Stage I- Stomatitis; erythematous mucosa, vesicles,
Stage II- Fibrosis in healing vesicles and ulcers;
blanching, palpable bands, mottled marble like
Stage III- Sequelae of OSMF; Leukoplakia, speech and
Lai DR 1995
Based on interincisal distance
Group 1- >35mm
Group 2- between 30 and 35mm
Group 3- between 20 and 30mm
Group 4- <20mm
Haider SM (2000)
Stage I: faucial bands only
StageII: faucial and buccal bands
Stage III: Faucial, buccal and labial bands.
I. Mouth opening ≥ 20 mm.
II. Mouth opening 11-19 mm.
III. Mouth opening ≤10 mm.
Prakash R. et al
Based on morphologic variants of soft palate
Type 1: Leaf shaped
Type 2: Rat tail shaped
Type 3: Butt shaped
Type 4: Straight line
Type 5: Deformed S
Type 6: Crook shaped
• Grade I : Epithelium shows Hyperkeratosis, intra cellular
edema, little basal cell hyperplasia, rete ridges present.
Histological classification- Bailor D.N.
• Grade II : Epithelium undergoing atrophy, rete ridges less
prominent, connective tissue showing thickened collagen
bundles, less cellularity, fibrosed blood vessels with moderate
amount of hyalinization.
• Grade III : Marked atrophy of epithelium, absence of rete ridges,
connective tissue showing abundant hyalinization, cellularity
absent in connective tissue.
Systemic factors :
Genetic predisposition and
Epidemiological and in vitro experimental studies - chewing
areca nut is the major etiological factor.
Capsaicin, an active principle, mild irritant, which brings about
epithelial and connective tissue changes in OSMF patients.
Elastic degradation of collagen and ultrastructurally, partial or
complete degeneration of collagen into elastin-like filaments,
sheets or dense amorphous material. (Sirsat & Khanolkar 1960).
Mutogenic and enhance the tumorigenicity of tobacco in
experimental animals. (Bhide 1992)
Increases the risk of cancers in the upper aero digestive
tract in a dose- dependent manner. (Notani 1992)
May be secondary
OSMF patients cannot tolerate spicy food & the opening of
the mouth in OSF patients becomes smaller which may affect
normal food intake and lead to nutritional deficiencies.
Four alkaloids- Arecoline, Arecaidine, Guvacine, Guvacoline.
Arecoline – main agent. (Tilakaratne 2006).
Flavanoid components- tannins and catechins.
Fibroblastic proliferation and inceased collagen formation.
Chronic placement of betel quid (areca nut)
Rigidity & limited mouth opening
ROLE OF ARECOLINE
( Slaked lime) (Hydrolysis )
Fibroblast stimulation & proliferation
Increased collagen synthesis
Large quantity of tannin present in areca nut
Reduced collagen degradation
Stabilization of collagen by tannins (and catachins polyphenols)
Arecoline + tannin → ↓ degradation of collagen
↑ production of collagen
Increased generation of ROS
Activates various transcription factors
( NF kappa B, JNK & p38 MAPK)
Stimulates CTGF (fibroblasts and
Fibroblastic proliferation and increased
Increased production of Tissue inhibitors of
Inhibits activated collagenase
Increased production of collagen/decreased
degradation of collagen
Presence of Copper in nut:
Copper content in areca nut
( Increased activity of lysyl
oxidase enzyme )
Fibroblast stimulation &
Increased collagen synthesis
MATRIX METALLOPROTEINASES AND TISSUE
INHIBITORS OF MATRIX METALLOPROTEINASES
Increased ROS and DNA double strand breaks produced
by damaged mitochondria
TIMP-1 & 2/ MMP-1
Collagen production / collagen degradation
Increased levels of cytokines in the lamina
Induce development of disease
TGF-ß Platelet derived growth
Basic fibroblast growth
ACCUMULATION OF COLLAGEN AND
OTHER CHANGES IN ECM
Early stage – tenascin, fibronectin, perlecan and collagen type III
were enhanced in lamina propria and submucosa.
Intermediate stage – elastin extensively and irregularly deposited
around muscle fibres together with above mentioned molecules
Advanced stage – all the ECM molecules get decreased and
replaced by collagen type I
Heat shock protein (HSP 47) is a collagen specific molecular
chaperone involved in the processing and/or secretion of
procollagen. HSP 47 is significantly upregulated in OSF. Arecoline
was found to elevate HSP 47 expression in fibroblasts.
Cystatin C, a non glycosylated basic protein is increased in a
variety of fibrotic diseases, Cystatin C was found to be
upregulated both at m–RNA and protein levels in the disease.
Arecoline is responsible for this enhancement in a dose
EPITHELIAL MESENCHYMAL TRANSITION (EMT)
ANE caused cell injury
MAPK & NF kB pathways involved in EMT
Alteration of normal keratinocyte
Keratinocytes PGE2, IL-6, TNFα and TGFβ
ANGIOGENESIS RELATED MOLECULES
Overexpression of iNOS, b-FGF, TGF-β, PDGF, HIF-1α
Maintain vascularity of underlying CT
Adaptive response of mucosa to cope up with the
hypoxia caused by fibrosis
Reduction in vascularity
atrophy & ulceration overexpression of HIF-1α
ALTERATIONS OF CELL CYCLE
PCNA index is higher in OSF epithelium than normal oral mucosa
– increased malignant transformation potential.
Important molecules in G2/M phase ( cyclin B1, p34 and p-
survivin) are over expressed malignant transformation by
inhibition of apoptosis and encouraging mitosis in carcinogenesis.
Survivin as both prognostic and predictive marker in malignant
transformation of OSF
Genomic instability (LOH)
Absence of tumor suppressor genes
Malignant transformation of OSF
EARLY OSMF ADVANCED OSMF
Defective gustatory sensation
Dryness of mouth
White fibrous bands (vertically)
Fixation, shortening or deviation of uvula
Impairment of tongue movement
Inability to blow or whistle
Difficulty in swelling
Blanching seen over left
Blanching seen on
ventral surface of
tongue, floor of
mouth and restricted
movements of tongue
opening in oral
Soft palate and
Soft palate showing
shrunken uvula seen in
the posterior part
Histological findings in OSMF cases were found to vary depending
on the clinical severity of the cases and the site of biopsy
The observed epithelial changes are secondary to changes in
The findings range from normal to atrophic and hyperplastic
epithelium (Sirsat & Khanolkar, 1957).
Pindborg and Sirsat (1966) observed marked changes in the form of
atrophy of epithelium with loss of rete pegs in 90% of the cases as
compared to normal oral mucosa.
The atrophic epithelium also exhibits intracellular edema, signet
cells and epithelial atypia (focal dysplasia).
Epithelial keratinization, especially the tendency of atrophic and
hyperplastic epithelium to show keratinization was higher when
compared to normal.
Increased mitotic activities were evident in a small number of
Classical oral submucous fibrosis (OSMF) showing thin atrophic
epithelium with chronic inflammation and dense fibrosis in the
submucosa (hematoxylin-eosin, original magnification 200).
CONNECTIVE TISSUE CHANGES
Pindborg et al (1966) have described four consecutive stages in
submucous fibrosis cases based on sections stained with
haemotoxylin and eosin:
The changes are based on following criteria
Presence or absence of edema
Nature of the collagen bundles
Overall fibroblastic response
State of the blood vessels
Predominant cell type in the inflammatory exudates
Very early stage
Fine fibrillar collagen dispersed with marked edema and
strong fibroblastic response showing plump young fibroblasts
containing abundant cytoplasm will be observed.
Blood vessels - occasionally normal, but more often they are
dilated and congested.
Inflammatory cells- polymorphonuclear leukocytes with
occasional eosinophils, are present.
In this stage juxta-epithelial area shows early hyalinization.
The collagen is still seen as separate bundles which are
Plump young fibroblasts are present in moderate numbers.
The blood vessels are often dilated and congested.
The inflammatory cells are mostly lymphocytes, eosinophils
and the occasional plasma cells.
Histopathological picture showing early changes in
the oral submucous fibrosis
Moderately advanced stage
In this stage, the collagen is moderately hyalinised.
The amorphous change starts from the juxta-epithelial basement
Occasionally, thickened collagen bundles are still seen
separated by slight residual edema.
The adult fibroblastic cells have elongated spindle shaped nuclei
and scanty cytoplasm.
Blood vessels are either normal or constricted as a result of
increased surrounding tissue.
The inflammatory exudate consists of lymphocytes, plasma cells
and occasional eosinophils.
The collagen is completely hyalinised and is seen as a
smooth sheet with no distinct bundles or edema
Hyalinised connective tissue becomes hypocellular with thin
Blood vessels are completely obliterated or narrowed.
The inflammatory exudate consists of lymphocytes and
plasma cells and occasional eosinophils.
Interestingly the melanin containing cells in the lamina propria
are surrounded by dense collagen, which explains the
clinically observed loss of pigmentation.
Histopathological picture of advanced stage oral submucous
fibrosis showing atrophied epithelium, increased fibrosis and
hyalinization of submucosal tissues
Khanna and Andrade (1995); grouped OSMF features into 4
groups based on histopathological features:
Group I : Very early changes
Common symptom is burning sensation in the mouth.
Acute ulceration and recurrent stomatitis
Not associated with mouth opening limitation.
Fine fibrillar collagen network interspersed with marked edema.
Blood vessels dilated and congested.
Large aggregate of plump, young fibroblasts present with
Inflammatory cells mainly consist of polymorphonuclear
leukocytes with few eosinophils.
Group II : Early cases
Buccal mucosa appears mottled and marble-like
Widespread sheets of fibrosis palpable
Patients with an interincisal distance of 26-35mm
Juxtaepithelial hyalinization present
Collagen present as thickened but separate bundles.
Blood vessels dilated and congested
Young fibroblasts seen in moderate number
Inflammatory cells mainly consist of polymorphonuclear
leukocytes with few eosinophils and occasional plasma cells.
Flattening or shortening of epithelial rete pegs evident with
varying degree of keratinization.
Group III : Moderately advanced cases
Trismus evident with an interincisal distance of 15-25mm
Buccal mucosa appears pale and firmly attached to underlying
Atrophy of vermilion border
Vertical fibrous bands palpable at the soft palate,
pterygomandibular raphe and anterior faucial pillars.
Juxtaepithelial hyalinization present
Thickened collagen bundles faintly discernible, separate by very
slight, residual edema.
Blood vessels, mostly constricted
Mature fibroblasts with scanty cytoplasm and spindleshaped nuclei
Inflammatory exudates consists mainly of lymphocytes
Epithelium markedly atrophic with loss of rete pegs
Muscle fibers seen interspersed with thickened and dense
Group IV A : Advanced cases:
Trismus is severe with interincisal distance of less than 15mm
The fauces are thickened, shortened and firm on palpation.
Uvula is shrunken and appears as a small, fibrous bud
Tongue movements are limited
On palpation of lips, circular band felt around entire mouth.
Group IV B:
Advanced cases with premalignant and malignant changes.
Hyperkeratosis, leukoplakia, or squamous cell carcinoma can
Collagen hyalinized as smooth sheet.
Extensive fibrosis obliterating the mucosal blood vessels and
eliminating the melanocytes.
Fibroblasts markedly absent within the hyalinized zones.
Total loss of epithelial rete pegs.
Mild to moderate atypia present.
Extensive degeneration of muscle fibers evident
(a) Loss of striation in muscle; (b) Floculant material
OSMF showing extensive fibrosis in the submucosa
(hematoxylin-eosin, original magnification 200).
OSMF with lichenoid reaction, showing bandlike
inflammatory exudate with fibrosis (hematoxylin-
Van Gieson's Stain
Heat shock proteins 47
Endothelial markers- CD31,
Basic fibroblastic growth factor
The precancerous nature of OSF was first discovered by
Paymaster (1956), when he observed slow growing
squamous cell carcinoma in one third of the patients with the
This was confirmed with various groups & Pindborg (1972)
put forward five criteria to prove that the disease is
precancerous. They included:
1. High occurrence of OSF in oral cancer patients
2. Higher incidence of squamous cell carcinoma in patients with
3. Histological diagnosis of cancer without any clinical suspicion
4. High frequency of epithelial dysplasia &
5. Higher prevalence of leukoplakia among OSF.
Malignant transformation rate of OSF was found to be in the
range of 7–13% (Tilakaratne 2006).
According to long-term follow-up studies a transformation rate
of 7.6% over a period of 17 years was reported (Murti1985).
Blood chemistry and haematological variations.
Iron, vitamin B12, folate levels
ESR, anemia and eosinophilia,
1) Restriction of habits:
Reduction or elimination of habit of areca nut chewing is an
important preventive measure.
suppresses inflammatory response by their anti-inflammatory
It prevents fibrosis by decreasing fibroblastic proliferation and
deposition of collagen.
local injection (intralesional injection), topical applications or
in the form of mouth washes.
Break down hyaluronic acid, lower the viscosity of the
intercellular cement substance and also decreases collagen
Intralesional injection of Hyalase used in the dose of 1500 IU,
Chymotrypsin 5000 IU, Fibrinolytic agents (Hyalase) dissolved in
4) Placental Extracts:
The combination of dexamethasone, hyaluronidase and placental
extract were found to give better results than with a single drug
5) Nutritional support: High proteins, calories, vitamin B complex,
other vitamins and minerals.
6) Physiotherapy: forceful mouth openings, heat therapy.
7) Surgical treatment: cutting the fibrotic bands resulted in more
fibrosis and disability.
Excision of fibrotic tissues and covering the defect with split
thickness skin, fresh human amnion or buccal fat pad (BFP) grafts
have been applied to treat OSMF
8) Stem cell therapy
Recently scientists have proven that intralesional injection
of autologous bone marrow stem cells is a safe and effective
treatment modality in oral sub mucosal fibrosis.
Autologous bone marrow stem cell injections
induces angiogenesis in the area of lesion which in turn
decreases the extent of fibrosis thereby leading to significant
increase in mouth opening
In summary, the available literature indicates that the main
aetiological factors for OSF are the constituents of areca nut,
mainly arecoline, whilst tannin may have a synergistic role.
The use of Areca nut should be avoided in commercial
smokeless tobacco products. It is an urgent need to educate
people about the adverse effects regarding oral cavity.
Future research should also focus on targeting various
molecules and pathways which have been identified, in order
to search for effective treatment as morbidity and mortality is
significantly higher in OSF.
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