this seminar emphasizes abour osmf,historical background,nearly all classification were covered,its pathogenesis starting from physical changes to cellular changes in oral mucosa and treatment modalities

1. BY :
GAURAV KATHERIYA

2. Introduction
History
Definition
Epidemiology
Nomenclature
Classification
Etiopathogenesis
Clinical features
Histopathology
Differential diagnosis
Special investigations
Malignant potential
Treatment and Management

3. INTRODUCTION
 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 irritations.
 In response to these stresses, both epithelium and
connective tissue layers of the oral mucosa exhibit acute
and chronic reactive changes.

4.  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
juxtra-epithelial inflammatory reaction along with mucosal fibrosis.
 OSMF is characterized by deposition of dense collagen in the
connective tissue

5. HISTORY
 The condition of oro -pharyngeal OSMF of oral cavity was
prevalent even in the days of Shushrutha (600 B.C).
 Shushrutha, the greatest practitioner of ancient medicine stated
in his book "Shushrutha Samhita' a condition called 'VIDARI'
in his classification of diseases of mouth and throat.
 The features of VIDARI suit the symptomatology of OSMF.

6.  First described among five East African women of Indian origin
under the term Atrophia idiopathica (tropica) Mucosae Oris by
Schwartz 1952
 Joshi in 1953 is credited to be the first person who described it
and gave the present term “Oral sub-mucous fibrosis”.
 In the year 1954, Su from Taiwan described a similar condition,
which he called "Idiopathic Scleroderma of mouth"

7.  Paymaster (1956) described the pre-cancerous nature of the condition.
Other names that have been suggested are:
• Diffuse oral sub-mucous fibrosis (Lal D.1953)
• Sclerosing stomatitis (Behl 1962)
 Idiopathic palatal fibrosis (Rao 1962)

8. DEFINITION:
(J.J Pindborg and Sirsat 1966)
 It is an insidious chronic disease affecting any part of the
oral cavity and sometimes the pharynx. Although occasionally
preceded by and/or associated with vesicle formation ,it is
always associated with juxtra-epithelial inflammatory reaction
followed by a fibro-elastic changes of the lamina propria with
epithelial atrophy leading to stiffness of the oral mucosa and
causing trismus and inability to eat.

9. EPIDEMIOLOGY
 Oral submucous fibrosis (OSF), first described in the early 1950s, is a
potentially malignant disease predominantly seen in people of Asian
descent.
 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..
 Pindborg (1980) quotes it as almost exclusively occurring among
Indians, Pakistanis and Burmese.

10.  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 and pain.
 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)
 2.3:1- M:F

11. NOMENCLATURE
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
Desa 1957 Submucous fibrosis of palate and check
George 1958 Submucous fibrosis of palate and mucosa
membrane
Pindborg& Sirsat 1964 Oral submucous fibrosis
Goleria 1970 Sub-epithelial fibrosis

12. CLASSIFICATION
A. Classifications based on clinical features of OSMF are
as follows:
• JV Desa (1957)
• Pindborg JJ (1989)
• SK Katharia et al (1992)
• Lai DR et al (1995)
• R Maher et al (1996)
• Ranganathan K et al (2001)

13. • Rajendran R (2003)
• Nagesh and Bailoor (2005)
• Tinky Bose and Anita Balan (2007)
• Kiran Kumar et al (2007)
• Chandramani More et al (2011)
B. Classifications based on histopathological features:
• Pindborg JJ and Sirsat SM (1966)
• Utsunomiya H et al (2005)
• Kumar Kiran et al (2007)

14. C. Classification based on clinical and histopathological
features:
• Khanna JN et al (1995)

15. A. Classification based on clinical features of OSMF:
JV Desa (1957) divided OSMF into three stages as follows:
– Stage I: Stomatitis and vesiculation
– Stage II: Fibrosis
– Stage III: As its sequelae

16. Pindborg JJ (1989) divided OSMF into three stage:
 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 hallmark of this stage.
 Stage 3: Sequelae of OSMF are as follows:

17.  Leukoplakia is found in more than 25 % of the individuals with
OSMF.
 Speech and hearing defects may occur due to involvement of the
tongue and eustachian tubes.

18. S K Katharia et al (1992) have given different scores assigned to the
patients on the basis of mouth opening:
 between upper and lower central incisors as follows
 Score 0: Mouth opening is 41 mm or more.
 Score 1: Mouth opening is 37 to 40 mm.
 Score 2: Mouth opening is 33 to 36 mm.
 Score 3: Mouth opening is 29 to 32 mm.

19.  Score 4: Mouth opening is 25 to 28 mm.
 Score 5: Mouth opening is 21 to 24 mm.
 Score 6: Mouth opening is 17 to 20 mm.
 Score 7: Mouth opening is 13 to 16 mm.
 Score 8: Mouth opening is 09 to 12 mm.
 Score 9: Mouth opening is 05 to 08 mm
 Score 10: Mouth opening is 0 to 04 mm.

20. Lai Dr (1995) divided OSMF based on the inter-incisal distance as
follows:
 Group A: >35 mm
 Group B: Between 30 and 35 mm
 Group C: Between 20 and 30 mm
 Group D: <20 mm

21.  R Maher et al (1996) had given criteria for evaluation of interincisal
distance as an objective criterion of the severity of OSMF in Karachi,
Pakistan. In his study, he divided intraoral regions into eight
anatomical subregions viz palate, posterior one-third of buccal
mucosa, mid one-third of the buccal mucosa, anterior one-third of
buccal mucosa, upper labial mucosa, tongue and floor of mouth and
looked for disease involvement in each to assess the extent of clinical
disease.

22. This was further grouped into three categories as follows:-
 – Involvement of >1/3rds of the oral cavity(if three or less of
the above sites are involved).
 – Involvement of 1-2/3rds of the oral cavity (if four to six
intraoral sited are involved).
 – Involvement of <2/3rds of the oral cavity (if more than six
intraoral sites are involved).

23.  Ranganathan K et al (2001) divided OSMF based
on mouth opening as follows:
 – 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.Precancerous or cancerous changes seen throughout the
mucosa.

24.  Rajendran R (2003) reported the clinical features of
OSMF as follows:
 – Early OSF: Burning sensation in the mouth.
 Blisters especially on the palate, ulceration or recurrent generalized
inflammation of oral mucosa, excessive salivation, defective gustatory
sensation and dryness of mouth.
 – Advanced OSF: Blanched and slightly opaque mucosa, fibrous bands
in buccal mucosa running in vertical direction. Palate and faucial
pillars are the areas first involved. Gradual impairment of tongue
movement and difficulty in mouth opening.

25.  Nagesh and Bailoor (1993) based on diagnosis :
 Stage I early OSMF: Mild blanching, no restriction in
 mouth opening (normal distance between central incisor tips: Males 35
to 45 mm, females 30 to 42 mm), no restriction tongue protrusion.
 Stage II moderate OSMF: Moderate to severe blanching,mouth
opening reduced by 33%, cheek flexibility also demonstrably reduced,
burning sensation also in absence of stimuli, palpable bands felt.

26.  Lymphadenopathy either unilateral or bilateral and demonstrable
anemia on hematological examination.
Stage III severe OSMF: Burning sensation is very severe
 patient unable to do day-to-day work, more than 66% reduction in the
mouth opening, cheek flexibility and tongue protrusion. Tongue may
appear fixed. Ulcerative lesions may appear on the cheek, thick
palpable bands and lymphadenopathy bilaterally evident.

27.  Tinky Bose and Anita Balan (2007) had given clinical classification,
categorized the patients into three groups based on their clinical
presentations:
 Group A—mild cases: Only occasional symptoms,pallor, vesicle
formation, presence of one or two solitary palpable bands, loss of
elasticity of mucosa, variable tongue involvement with protrusion
beyond vermillion border. Mouth opening >3 cm.
 Group B—moderate cases: Symptoms of soreness of mucosa or
increased sensitivity to-

28.  chilies, diffuse involvement of the mucosa,blanched appearance,
buccal mucosa tough and inelastic fibrous bands palpable,
considerable restriction of mouth opening (1.5 to 3 cm) and
variable tongue movement.
Group C—severe cases: Symptoms more severe,
 broad fibrous bands palpable, blanched opaque mucosa, rigidity
of mucosa, very little opening of mouth (less than 1.5 cm),
depapillated tongue and protrusion of tongue very much
restricted

29.  Kiran Kumar et al (2007) categorized three clinical stages of
OSMF on the basis of mouth opening as follows:
 – Stage I: Mouth opening >45 mm
 – Stage II: Restricted mouth opening 20 to 44 mm
 – Stage III: Mouth opening <20 mm

30.  Chandramani More et al (2011):
 – Clinical staging:
 - Stage 1 (S1): Stomatitis and/or blanching of oral mucosa.
 - Stage 2 (S2): Presence of palpable fibrous bands in buccal mucosa
and/or oropharynx, with /without stomatitis.
 - Stage 3 (S3): Presence of palpable fibrous bands in buccal mucosa
and/or oropharynx, and in any other parts of oral cavity, with/without
stomatitis.

31. Stage 4 (S4) as follows:
 a. Any one of the above stage along with other potentially malignant
disorders, e.g. oral leukoplakia, oral erythroplakia, etc.
 b. Any one of the above stage along with oral carcinoma.
 – Functional staging:
 - M1: Interincisal mouth opening up to or greater than 35 mm.
 - M2: Interincisal mouth opening between 25 and 35 mm.
 - M3: Interincisal mouth opening between 15 and 25 mm.
 - M4: Interincisal mouth opening less than 15mm.

32.  2. Classifications based on histopathological features of
 OSMF:
 • Pindborg JJ and Sirsat SM (1966) were the first to divide OSMF
depending only on histopathological features alone are as follows:
 – Very early stage: Finely fibrillar collagen dispersed with marked
edema. Plump young fibroblast containing abundant cytoplasm. Blood

33.  vessels are dilated and congested. Inflammatory cells, mainly
polymorphonuclear leukocytes with occasional eosinophils are found.
 – Early stage: Juxta-epithelial area shows early 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.

34.  – 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.

35.  Advanced stage: Collagen is completely hyalinized. Smooth sheets
with no separate bundles of collagen is seen.
 Edema is absent.
 Hyalinized area is devoid of fibroblasts.
 Blood vessels are completely obliterated or narrowed.
 Inflammatory cells are lymphocytes and plasma cells.

36.  Utsunomiya H, Tilakratne WM, Oshiro K et al(2005) histologically
divided OSMF based on the concept of Pindborg and Sirsat and
modified it as follows:
 – Early stage: Large number of lymphocytes in subepithelial,
connective tissue, zone along with myxedematous changes.
 – Intermediate stage: Granulation changes close to the muscle layer
and hyalinization appears in subepithelial zone where blood vessels are
compressed by fibrous bundles. Reduced inflammatory cells in
subepithelial layer.

37.  Advanced stage: Inflammatory cell infiltrate hardly seen. Number of
blood vessels dramatically small in subepithelial zone.
Marked fibrous areas with hyaline changes extending from
subepithelial to superficial muscle layers.
Atrophic, degenerative changes start in muscle
fibers.

38.  Kiran Kumar et al (2007) proposed histological grading as follows:1
 – Grade I: Loose, thick and thin fibers
 – Grade II: Loose or thick fibers with partial hyalinization
 – Grade III: Complete hyalinization

39.  Classification based on clinical and histopathological
features:
 Khanna JN and Andrade NN (1995) developed a group
classification system for the surgical management of OSMF.16
 – Group I:
 - Very early cases: Common symptom:-
 Burning sensation in the mouth,
 Acute ulceration and recurrent stomatitis
 Not associated with mouth opening limitation.

40.  - Histology: Fine fibrillar collagen network interspersed with
marked edema, blood,vessels dilated and congested, large aggregate
of plump young fibroblasts present with abundant cytoplasm,
inflammatory cells mainly consist of polymorphonuclear leukocytes
with few eosinophils. The epithelium is normal.

41.  Group II: Early cases—Buccal mucosa appears mottled and marble
like, widespread sheets of fibrosis palpable, interincisal distance of 26
to 35 mm.
 - Histology: Juxta-epithelial 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.

42.  Group III: Moderately advanced cases—
 Trismus, interincisal distance of 15 to 25 mm,buccal mucosa appears
pale firmly attached to underlying tissues, atrophy of vermilion border,
 vertical fibrous bands palpable at the soft palate,pterygomandibular
raphe and anterior faucialpillars.

43.  - Histology:
Juxta-epithelial hyalinization present, thickened collagen
bundles, residual edema, constricted blood vessels, mature
fibroblasts with scanty cytoplasm and spindle-shaped nuclei,
inflammatory exudate which consists of lymphocytes and plasma
cells, epithelium markedly atrophic with loss of rete pegs, muscle
fibers seen with thickened and dense collagen fibers

44. Group IVA: Advanced cases—severe trismus,
 interincisal distance of less than 15 mm,
 thickened faucial pillars, shrunken uvula
 restricted tongue movement, presence of circular
 band around entire lip and mouth.
 Group IVB: Advanced cases—presence of
 hyperkeratotic leukoplakia and/or squamous cell
 carcinoma.

45. Histology:
Collagen hyalinized smooth sheet,extensive fibrosis,
obliterated the mucosal blood vessels, eliminated
melanocytes, absent fibroblasts within the hyalinized zones,
total loss of epithelial rete pegs, presence of mild to
moderate atypia and extensive degeneration of muscle
fibers.

46. 46
• 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.

48. etioPATHOGENESIS

49. ETIOLOGY
 Multifactorial
 Local factors:
Chillies and
Arecanut
 Systemic factors :
Nutritional deficiency,
Genetic predisposition and
Autoimmunity.
 Epidemiological and in vitro experimental studies - chewing areca nut is
the major etiological factor.

50. Chillies-
 Capsaicin, an active principle is a 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).

51. ARECA NUT
 made up of alkaloid and flavonoid components.
 Four alkaloids namely arecoline, arecaidine, guvacine,
and guvacoline have been identified in areca nut,
 of which arecoline is the most potent agent.
 plays a major role in the pathogenesis of OSF by causing
an abnormal increase in collagen production

52. ROLE OF ARECOLINE
Arecoline
( Slaked lime) (Hydrolysis )
Arecaidine
Fibroblast stimulation & proliferation
Increased collagen synthesis

53. Basic mechanisms involved in the
pathogenesis of OSF can be divided
into four steps:
1. Occurrence of the chronic inflammation at the site of
betel quid placement
2. Increased collagen synthesis
3. Collagen cross-linking
4. Decreased collagen degradation

54. 1. Occurrence of the chronic
inflammation at the site of betel
quid placement:

56. 1. INCREASED COLLAGEN SYNTHESIS

57. Collagen cross-linking:

58.  High levels of copper have been demonstrated in areca nut.
 Chewing areca nut for 5 – 30 minutes increases the soluble
copper levels in the oral fluids which in turn stimulates
fibrogenesis through up-regulation of LOX activity.
 Flavonoids present in the areca nut also play an important role
in the process of enhancing the cross-linking of the fibers. It
has been demonstrated in in-vitro studies that presence of
catechin raises the LOX activity

59. Decreased Degradation of collagen:

60. 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

61.  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 dependent manner

62. HYPOXIA
Extensive fibrosis
Reduction in vascularity
Hypoxia
atrophy & ulceration overexpression of HIF-1α
malignant transformation

63. 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

64. GENETIC SUSCEPTIBILITY
Genomic instability (Loss Of heterozygosity)
Absence of tumor suppressor genes
Malignant transformation of OSF

65. • Increased K1, K10 and K17
in suprabasal layers
• Increased K6 and complete
loss of K17 in basal layer
• Complete loss of K19 in the
epithelium.
Excessive fibrosis
of subepithelial
CT can effect the
overlying
epithelium

66. CLINICAL FEATURES
EARLY OSMF ADVANCED OSMF
Burning sensation
Blisters
Ulcerations
Excessive salivation
Defective gustatory sensation
Dryness of mouth
Blanced
Slightly opaque
White fibrous bands (vertically)
Fixation, shortening or deviation of uvula
Impairment of tongue movement
Inability to blow or whistle
Difficulty in swelling
Nasal voice

67. Blanching seen over left buccal
mucosa
Blanching seen on ventral surface
of tongue, floor of mouth and
restricted movements of tongue

68. Decreased mouth opening in
oral submucous fibrosis
patient
Soft palate and faucial pillars
showing redness

69. Soft palate showing blanching and
shrunken uvula seen in
the posterior part

70. Histopathology
 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
connective tissue.
 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.
EPITHELIAL CHANGES

71.  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 cases

72. Classical oral submucous fibrosis (OSMF) showing thin atrophic
epithelium with chronic inflammation and dense fibrosis in the
submucosa (hematoxylin-eosin, original magnification 200).

73. 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

74. 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.

75. Early stage
 In this stage juxtra-epithelial area shows early hyalinization.
 The collagen is still seen as separate bundles which are thickened.
 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.

76. Histopathological picture showing early changes in the oral submucous
fibrosis

77. Moderately advanced stage
 In this stage, the collagen is moderately hyalinised.
 The amorphous change starts from the juxta-epithelial basement
membrane.
 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.

78. Advanced stage
 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 elongated
cells.
 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.

79. Histopathological picture of advanced stage oral submucous fibrosis showing
atrophied epithelium, increased fibrosis and hyalinization of submucosal tissues

80. (a) Loss of striation in muscle; (b) Floculant material
showing degeneration

81. OSMF showing extensive fibrosis in the submucosa (hematoxylin-
eosin, original magnification 200).

82. OSMF with lichenoid reaction, showing bandlike
inflammatory exudate with fibrosis
(hematoxylin-eosin).

83. SPECIAL INVESTIGATIONS
SPECIAL STAINS
Van Gieson's Stain
Masson's trichrome
stain
Picrosirius red
IHC MARKERS
Heat shock proteins 47
Cystatin c
Survivin
Endothelial markers- CD31,
CD34, CD105
Basic fibroblastic growth factor
P53
Bcl-2
Ki-67

84. DIFFERENTIAL DIAGNOSIS
 Trismus
 Oral lichen planus
 Scleroderma
 Fibroma
 Generalized fibromatosis
 Anemia
 Amyloidosis

85. MALIGNANT POTENTIAL
 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 disease.

86.  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 OSF
3. Histological diagnosis of cancer without any clinical suspicion in
OSF
4. High frequency of epithelial dysplasia &
5. Higher prevalence of leukoplakia among OSF.

87.  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).

88. BIOLOGICAL STUDIES
Blood chemistry and haematological variations.
Iron, vitamin B12, folate levels
ESR, anemia and eosinophilia, gammaglobulin

89. TREATMENT
1) Restriction of habits:
Reduction or elimination of habit of areca nut chewing is an important
preventive measure.
2) Corticosteroids:
suppresses inflammatory response by their anti-inflammatory action.
It prevents fibrosis by decreasing fibroblastic proliferation and deposition
of collagen.
local injection (intralesional injection), topical applications or in the form of
mouth washes.

90. 3) Hyaluronidase:
Break down hyaluronic acid, lower the viscosity of the intercellular cement
substance and also decreases collagen formation.
Intralesional injection of Hyalase used in the dose of 1500 IU, Chymotrypsin 5000
IU, Fibrinolytic agents (Hyalase) dissolved in 2% lignocaine.
4) Placental Extracts:
The combination of dexamethasone, hyaluronidase and placental extract were found
to give better results than with a single drug

91. 5) Nutritional support: High proteins, calories, vitamin B complex, other
vitamins and minerals.lycopene-6 -8 mg twice a day for 2 months
6) Physiotherapy: forceful mouth openings, heat therapy.
7) Surgical treatment:
A. Surgical Excision of Fibrous bands along with split thickness skin
graft
B. Surgical Excision of Fibrous bands along with fresh ammonia Graft
C. Surgical Excision of Fibrous band along with pedicled buccal fat pad
graft

92. 8) hyperbaric oxygen therapy: a.HBOT may be useful in the treatment
for OSF by promoting fibroblast apoptosis and inhibiting fibroblast
activation.
b. inhibite TNF-α and influencing the synthesis of collagenase.
c. TGF-β expression, IFN secretion and the growth of fibroblasts
decreased after chronic exposure to HBOT

93. 9) 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

94. 10.Pentoxifylline therapy: Pentoxifylline is a trisubstituted
methylxanthine derivative, the biologic activities of which are
numerous. This includes increasing red cell deformability,
leukocyte chemotaxis, antithrombin and anti- plasmin
activities, and more importantly to the present context, its
fibrinolytic activity
Dose-400 mg 3 times a day for 6 months

95. 11.Chymotrypsin-Chymotrypsin, an endopeptidase, hydrolyses
ester and Peptide bonds, thus acting as a proteolytic and anti-
inflammatory agent.
12.Interferon gamma-This plays a role in treatment of patients with
OSMF because of its immino regulatory effect. INTERFERON-
GAMMA is also known as anti fibrotic cytokine, patients treated
with an intralesional injection of interferon gamma experienced
improvement of symptoms.

96.  Intralesional injection of interferon gamma (0.01–10.0 U/mL)
3 times a day for 6 months

97.  13. Immune Milk-Immune milk contains an anti
inflammatory component that may suppress the
inflammatory reaction and modulate cytokine production.
Symptomatic relief in patients maybe partially attributed
to mice nutrients contained in the immune milk powder.
 14.diathermy-Microwave diathermy seem superior to short
wave, because selective heating of juxtaepitheliel connective
tissue is possible it acts by physio fibrinolysis of bands.

98.  15.CUCURMIN
 1, 7-bis (4-hydroxy-3-methoxyphenol)-1, 6-heptadiene-3, 5-
dione, is the primary active substance isolated from Curcuma
Longa L. rhizome
 inexpensive, widely available and has almost no side effects; it has
been long used as a spice and pigment in food processing industry.
 Curcumin has some important biological properties such as anti-
inflammatory, antioxidant and anti-cancer acticity(Goel et al., 2008).
 Recently, many studies have reported curcumin’s role in the prevention
and reduction of fibrosis caused by harmful factors (Venkatesan et al.,
2007; Osawa, 2007)

99.  significantly decreases the proliferation of fibroblasts and
myofibroblasts, in a dose-dependent manner.
 This effect is more pronounced in myofibroblasts; the growth
inhibitory rate for myofibroblasts incubated with curcumin was
double of that for the similarly treated fibroblasts
 It may be said that Curcumin activates mitochondrial enzymes that
lead to production of reactive oxygen species (ROS) and thatplays
crucial role in inhibition of myofibroblasts.

100. CONCLUSION
 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.

101. T
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