More of for Oral Medicne and Radiology

1. Binaya Subedi
Chitwan Medical College
BDS 4th
year, 4rd
batch

2. Introduction
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
connective tissue

3. First described by Schwartz “atrophica idiopathic mucosae oris” in
1952.
1953- Joshi from Bombay redesignated the condition as Submucous
Fibrosis.

4. Most widely accepted definition by Pindborg JJ & Sirsat S.M (1966) states-
“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”.
DEFINITION

5. EPIDEMIOLOGY
Oral submucous fibrosis (OSF), 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. 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.

6. 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

8. Based on clinical findings
Pindborg JJ 1989 classified OSMF as;
Stage I- Stomatitis; erythematous mucosa, vesicles,
ulcers, petechiae
Stage II- Fibrosis in healing vesicles and ulcers;
blanching, palpable bands, mottled marble like appearance
Stage III- Sequelae of OSMF; Leukoplakia, speech and
hearing deficit

9. Lai DR in 1995 classified it being based on
interincisal distance
Group 1- >35mm
Group 2- between 30 and 35mm
Group 3- between 20 and 30mm
Group 4- <20mm

10. 10
Haider SM (2000)
Clinical stage:
Stage I: faucial bands only
StageII: faucial and buccal bands
Stage III: Faucial, buccal and labial bands.
Functional stage:
I. Mouth opening ≥ 20 mm.
II. Mouth opening 11-19 mm.
III. Mouth opening ≤10 mm.

11. 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

12. 12
• 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.

15. 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.

16. Chillies-
 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.
 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)

17. Nutritional deficiencies
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.

18. Arecanut:
Four alkaloids- Arecoline,
Arecaidine, Guvacine, Guvacoline.
Arecoline – main agent.
(Tilakaratne 2006).
Flavanoid components- tannins
and catechins.
Fibroblastic proliferation and
inceased collagen formation.

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

20. Large quantity of tannin present in areca nut
Inhibits collagenases
Reduced collagen degradation
Stabilization of collagen by tannins (and catachins polyphenols)
Overall effect:
Arecoline + tannin degradation of collagen→ ↓
↑ production of collagen

21. Arecoline
Increased generation of ROS (oxidative
stress)
Activates various transcription factors
( NF kappa B, JNK & p38 MAPK)
Stimulates CTGF (fibroblasts and
endothelial cells)
Fibroblastic proliferation and increased
collagen formation.
It is also proposed that;

22. Arecoline
Increased production of Tissue inhibitors of
metalloproteinase (TIMP)
Inhibits activated collagenase
Increased production of collagen/decreased
degradation of collagen
Also;

23. Arecoline
altering
p53, checkpoint kinase
G2/M cell cycle arrest
Supresses endothelial cell population
Atrophy of epithelium & hypoxic environment
carcinogenesis

24. Arecoline + keratinocytes
differentiation
Fibroblast myofibroblast
ECM contraction
fibrosis
Trismus

25. Presence of Copper in nut:
Copper content in areca nut
( Increased activity of lysyl
oxidase enzyme )
Fibroblast stimulation &
proliferation
Increased collagen synthesis

26. MATRIX METALLOPROTEINASES AND TISSUE
INHIBITORS OF MATRIX METALLOPROTEINASES
Arecoline
Increased ROS and DNA double strand breaks produced by
damaged mitochondria
TIMP-1 & 2/ MMP-1
Collagen production / collagen degradation
fibrosis

27. 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

28. GENETIC SUSCEPTIBILITY
Genomic instability (LOH)
Absence of tumor suppressor genes
Malignant transformation of OSF

29. CLINICAL FEATURES
EARLY OSMF ADVANCED OSMF
•Burning sensation
•Blisters, vesicles
•Ulcerations
•Defective gustatory sensation
•Dryness of mouth
• Melanosis
• Petechiae
•Blanched
•Slightly opaque
•White fibrous bands (vertically)
•Fixation, shortening or deviation of uvula
•Impairment of tongue movement
•Inability to blow or whistle
•Difficulty in swallowing
•Nasal voice

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

31. Decreased mouth
opening in oral
submucous fibrosis
patient
(Normal= 45-65mm)
Soft palate and
faucial pillars
showing redness

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

34. 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.
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.
Epithelium normal.

35. Group II : Early cases
Buccal mucosa appears mottled and marble-like
Widespread sheets of fibrosis palpable
Patients with an interincisal distance of 26-35mm
Histology:
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.

36. Group III : Moderately advanced cases
Trismus evident with an interincisal distance of 15-25mm
Buccal mucosa appears pale and firmly attached to underlying tissues
Atrophy of vermilion border
Vertical fibrous bands palpable at the soft palate, pterygomandibular
raphe and anterior faucial pillars.
Histology:
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

37. Inflammatory exudates consists mainly of lymphocytes
Epithelium markedly atrophic with loss of rete pegs
Muscle fibers seen interspersed with thickened and dense collagen
fibers.

38. 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 be seen.

39. Histology:
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

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

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

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

43. Most of the times, OSMF can be distinguished from other
whitish lesions of oral cavity by proper history taking and local
examination of soft tissues.

44. 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

45. DIFFERENTIAL DIAGNOSIS
Scleroderma
Fibroma
Generalized fibromatosis
Anemia
Amyloidosis

46. 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.

47. 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.

48. 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).

50. Possible therapeutic interventions for OSF

51. 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.

52. 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

53. 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

54. 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

55. 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.

56. REFERENCES
 Neville Oral & maxillofacial pathology; 2nd
ed.
 Shafer’s textbook of oral pathology, 6th
ed.
 Burkit’s Oral Medicine, 12th
ed.

57. THANK YOU!!