1. ORAL SUBMUCOUS FIBROSIS

2. 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 juxta-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.

3. 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 which suit the symptomatology of OSMF.

4. 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. 1. P. from Taiwan described similar condition, which he called "Idiopathic Scleroderma of mouth"

5. 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)

6. EPIDEMIOLOGY
OSMF is a crippling fibrotic disorder seen commonly in India and Indian subcontinent. Sporadic cases are seen in Malaysia, Nepal, Thailand and South Vietnam.
Incidence of OSMF in India is % of population.
Persons between 20 and 40 years of age are most commonly affected ,but ages have ranged from 2 to 89 years of age
No cast or religious community is especially affected

7. Prevalence rate in India ranges from 0.2 to 1.2%
Case reports also include occurrence of this condition in a 4 yr old Indian immigrant girl in Canada, who had been chewing arecanut since the age of 2 yrs.
Prevalence rate in India ranges from 0.2 to 1.2%

8. ETIOLOGY

9. Etiology of OSMF: Exact etiology is unknown
Etiology of OSMF: Exact etiology is unknown. The suggested factors are, 1. Chronic Irritation Chilies Lime Betel nut Tobacco Chewing 2. Deficiency disease. 3. Defective iron metabolism 4. Bacterial Infection 5. Collagen disorder 6. Immunological disorders 7. Genetic disorder.

10. Chronic irritation:
Pathogenesis of OSMF lies in the continuous action of mild irritants.
Chillies:
"Capsaicin" a active extract from capsicum.
The active principle irritant of chillies (Capsicum annum and Capsicum frutescence) .

11. The suspicion that chilli is an etiological agent arose on the basis of ecological observations and was strengthened by the clinical and histological characteristics of this condition , i.e.
Blood eosinophilia,
Tissue eosinophils in the biopsy specimen and presence of sub epithelial vesicles
suggested an allergic nature of this disease possibly due to chilli intake.

12. There are some ecological arguments against the chilli hypothesis for example from Mexico or other South American countries where chilli consumption is widespread, there is no report of this condition.
The overall assessment is that there is no evidence substantiating the etiologic role of chilli in OSMF

13. Lime:
Betel nut & lime mixture is used for chewing. This also contains arecoline, lime and tannic acid, These cause local irritation and damage to the mucosa with vesicle and ulceration on susceptible individual.
Lime in betel quid causes constant aberration of oral mucosa, allowing direct access to the carcinogens

14. Tobacco Chewing
It is a known irritant and a causative factor in oral malignancies
N’-nitrosonornicotine is produced by bacterial and enzymatic nitrosation of nicotine and can be found by reaction of salivary nitrates with nornicotine
N’-nitrosonornicotine levels increased 44% when tobacco was mixed with saliva
N’-nitrosonornicotine extracted from chewing tobacco with saliva is approximately 1000 times that found in cigarette smoke

15. Betel nut:
Considered to be one of important etiological factor for OSMF
In India arecanut is chewed by itself or in the form of various areca nut preparations such as supari, mawa , manipuri , pan masala and in betel quid either with or without tobacco

16. The factors that contribute to the pathogenesis in habitual betel nut chewers. 1. The amount of tannic acid (14-18%) contained in the betel nut. 2. The influence of mixed calcium powder. 3. Action of arecoline contained in the betel nut affecting the vascular nerve of oral mucosa and causing neurotropic disorder

17. Arecanut contain different type of alkaloids- arecoline, arecadine, guvacoline, guvacine and isoguvacine.
Nitrosation of arecoline leads to the formation of arecanut specific nitrasamine. All arecanut specific nitrosamines are found to be powerful carcinogens and alkylate DNA.

18. The habit of chewing areca nut leads to muscle fatigue
KHANNA AND ANDHARA , have suggested pathogenesis of OSMF by dual action of arecanut. They suggested that ,
Arecoline , stimulate fibroblastic proliferation and collagen synthesis.
The flavonoids catechin and tannins stabilize the collagen fibrils rendering them resistant to degradation by collagenase.
The attendent trismus is a result of juxtaepithelial hyalinization and secondary muscle involvement (i.e. muscular degradation and fibrosis)
The habit of chewing areca nut leads to muscle fatigue

19. Deficiency disease
Vitamin B12 and Iron deficiency are associated with OSMF. The deficiency could be due to the fact that defective nutrition due to impaired food intake in advanced cases of OSMF, may be the effect rather than the cause of the disease

20. Defective iron metabolism
Impaired cellular utilization of iron explains the presence of hypochromic microcytic anemia. There is no definite proof to support the hypothesis that defective iron utilization by oral mucosa and sub-mucosa is the cause of OSMF

21. INFECTIONS Mukherjee and Biswas (1972) suggested that there is:
Rise in mucoprotein and mucopolysaccharide level
Rise in anti-streptolysin - O titre in OSMF patients.
(But these works are not confirmed)

22. Collagen disorder:
Rao (1962) suggested that OSMF is a localized condition of collagen disease.
He linked it to scleroderma, rheumatoid arthritis, duputreyens contracture and intestinal fibrosis. Histological features were found to be similar in OSMF and scleroderma.

23. HARMONAL FACTORS
There would appear to be predisposition in female with a ratio of women to men of 3:1
(Pillai R et al “pathogenesis of Oral submucous fibrosis”, cancer ;69: )

24. IMMUNOLOGICAL DISORDER:
Oral Submucous fibrosis is a high risk pre- cancerous condition. Raised ESR and globulin levels are found, indicative of immune inflammatory disorder.
Serum immunoglobulin levels IgA, IgG and IgM levels are raised. These suggest an antigenic stimulus in absence of any infection.
Increased circulating immune complex in OSMF

25. Genetic predisposition to the disease , involving the HLA antigens ,A10,DR3,DR7and probably B7 and the haplotypic pairs A10/DR3 and A10/B8 has been demonstrated.

26. The increased evidence of CD4 and HLA-DR-positive cells and high ratio of CD4 to CD8 in OSF tissue suggest an ongoing cellular immune response leading to imbalance of immunoregulation and alteration in local tissue architecture.

27. Mast cells
Mast cells are characterized by numerous cytoplasmic granules. Its cytoplasm contains mucopolysaccharides, histamine and heparin.
Many patients with early stage of OSMF give history of feeling of itching sensation which could be due to release of histamine exact role of mast cells in inflammation is not known.

28. IRREVERSIBLE FIBROSIS
MULTIFACTORIAL PATHOGENESIS
ARECANUT
TOBACCO
LIME
VOLATILE LIQUIDS
VOLATILE OILS
HYPERSENSITIVITY
MECHANICAL
TRAUMA
CHEMICAL BURN
TANNIN&
AFLOTOXIN
ARECOLINE
ALTERED IMMUNITY
GENETIC
REDISPOSITION
DEGRADATION
OF COLLAGEN
INCREASED SYNTHESIS
OF COLLAGEN
FIBROBLAST
FORMATION
IRREVERSIBLE FIBROSIS
CACINOMA
EXPOSURE CONTINOUS

29. Brief review : pathogenesis of OSMF
Section of fibroblasts with a high amount of collagen production during long term exposure to arecanut ingredients.
Stimulation of fibroblast proliferation and collagen synthesis by arecanut alkaloids or by fibrogenic cytokines secreted by activated macrophages and T lymphocytes in the OSF tissue

30. Decreased secretion of collagenase and deficiency in collagen phagocytosis by OSF fibroblasts
Production of collagen with a more stable structure (collagen type I trimer) by OSF fibroblast.
Stabilization of collagen structure by catechin and tannin from arecanut and an increase in collagen cross linkage caused by up regulation of lysy oxidase by OSF fibroblast

31. Malignant transformation rate is 7.6%
(JIAOM, vol-iv;no.3& 4 July-Dec.1993, p 12-15)

32. CLINICAL FINDINGS
The data regarding the sex predilection is conflicting. Earlier it was thought to be common in females.
But at present ,study ratio shows 2.3: 1 =M:F
Age group common is 2 to 3rd decade of life
But cases have been reported from 4 year to 86 yrs

33. Prodromal symptoms :
Onset is insidious. The most common initial symptoms are:
Burning sensation on eating spicy food
Blisters on the palate
Ulceration or recurrent stomatitis
Excessive salivation
Defective gustatory sensation
Dryness of mouth.

34. Later, Difficulty in opening mouth Inability to whistle, blow
Difficulty in swallowing
When fibrosis involves pharynx- referred pain to the ear.
Changes in tone of the voice due to vocal cord involvement
Some times deafness due to occlusion of eustachian tubes

35. Buccal mucosa, faucial pillars ,soft palate, lips and hard palate.
COMMON SITES INVOLVED
Buccal mucosa, faucial pillars ,soft palate, lips and hard palate.
The fibrous bands in the buccal mucosa run in a vertical direction ,sometimes so marked that the cheeks are almost immovable.
In the soft palate the fibrous bands radiate from the pterygomandibular raphe or the faucial pillars and have a sear like appearance

36. The faucial pillars become thick , short, and extremely hard.
The uvula is markedly involved , shrinks and appears as a small fibrous bud.
The faucial pillars become thick , short, and extremely hard.
The tonsils may be pressed between the fibrosed pillars
The lips are often affected and upon palpation , a circular band can be felt around the entire rima oris
When gingiva is affected , it is fibrotic, blanched and devoid of its normal stippled appearance.

37. BLANCHING LOWER LABIAL MUCOSA AND FLOOR OF MOUTH

38. INVOLVING LOWER LABIAL MUCOSA

39. UVULA SHRUNKEN GIVING HOCKEY STICK APPEARANCE

40. PALE AND BALD TONGUE

41. INTERINCISAL OPENING MEASUREMENT

42. SOFT PALATE

43. TRISMUS

44. Clinically signs of OSMF can be grouped as:
Stage I : Stage of stomatitis & vesiculation
Stage ll : Stage of fibrosis
Stage III : Stage of sequelae complication

45. Stage of stomatitis & vesiculation
It is earliest stage and characterized by recurrent stomatitis and vesiculation. Patient complaints of burning sensation in the mouth & inability to eat spicy food.
On examination vesicles on palate are seen.
They rupture and form superficial ulcers.
Some amount of fibrosis is also present.

46. Stage ll: Stage of fibrosis
There is inability to open mouth completely and stiffness in mastication. As disease advances there is difficulty in blowing out cheek & protruding tongue. Sometimes pain in ear and speech is muffled.On examination there in increasing amount of fibrosis in the submucosa. This causes blanching of mucosa.
Lips & checks become stiff & loose their normal resistance. Shortening & disappearance of uvula in advanced cases.
Dorsum of tongue shows atrophy of papillae.
Mucosa of floor of mouth show blanching & stiffness

47. Stage of sequelae & Complication
Patient presents with all the complaints as in stage II. Also there may be evidence of leukoplakia.
Changes in mucosa are whitish or brownish black-
Pindborg et al (1967) found the OSMF was found in 40%cases of oral cancer than in general population 1.2%.

48. CLINICAL GRADING OF SEVERITY OF OSMF
GRADE-I
Incipient
(very early stage)
GRADE-II
Mild
(early stage)
GRADE-III
Moderate
Moderately advanced stage
GRADE-IV
severe advanced stage
1.Burning sensation, dryness of mouth, vesicles or ulceration
1.Burning sensation, dryness of mouth
2.Irritation with
spicy food

49. 3.No change in mucosal colour
3. Oral mucosa is blanched and loses its elasticity
3.Blanched ,opaque, leather like mucosa
4. No fibrous bands
4. No clear cut fibrotic bands
4. Vertical fibrotic bands on buccal mucosa making it stiff
4. Thick fibrous bands occurring on both buccal mucosa, in retromolar area and at ptrygomandibular raphe
5. Mouth opening normal
5. Slight restriction of mouth opening
5.Considerable restriction of mouth opening
5. Very little mouth opening

50. 6.Tongue protrussion normal 6. Tongue protrussion not much affected
6.Restricted tongue protrussion
7.Difficulty in eating and speaking
7. Speech and eating very much impaired
8.Oral hygiene poor
8.Oral hygiene very poor

51. DIAGNOSIS IS BASED ON : Clinically discernible blanching and pallor
Palpable bands and restriction-of mouth opening.
Severe burning sensation of mouth, aggravated by use of even moderate spicy food.
Biopsy report characteristically showing histopathologically

52. Atrophic Oral epithelium. Loss of rete pegs .
Epithelial atypia may be observed.
Hyalinization of collagen bundles.
Fibroblasts decreased and blood vessels obliterated.

53. Stage 1: Early OSMF Mild blanching.
No restriction in mouth opening .Central incisor tip Males mm to tip of same side. Females 30-42mm.
No restriction in tongue protrusion .Mesio incisal angle of upper central incisor to the tip of the tongue when maximally extended with mouth wide open-Males 5- 6 cms and Females cms.

54. Moderate to severe blanching .
Stage 2 : Moderate OSMF…
Moderate to severe blanching .
Mouth opening reduced by 33%.Flexibility also demonstrably decreased.
Burning sensation even in absence of stimuli.
Palpable bands felt.
Lymphadenopathy either unilateral or bilateral.
Demonstrable anemia on hematological examination.

55. Burning sensation very severe. patient unable to do day to day work.
Stage 3: Severe OSMF
Burning sensation very severe. patient unable to do day to day work.
More than 66% reduction in the mouth opening cheek flexibility and tongue protrusion, the tongue may appear fixed.
Ulcerative lesions may appear on the cheek.
Thick palpable bands.
Lymphadenopathy bilaterally evident..

56. INVESTIGATIONS

57. Hyper gammaglobulinaemia Lower serum vitamin A levels
Lab findings reflect the nature of tissue changes in this condition rather than any diagnostic importance.
Increased ESR
Anemia
High eosinophil count
Hyper gammaglobulinaemia
Lower serum vitamin A levels

58. MANAGEMENT

59. MANAGEMENT Various modalities of treatment have been tried.
1.Restriction of habits/ Behavioral therapy
2. Medicinal therapy
3. Surgical therapy.
4. Oral Physiotherapy

60. Restriction of habits/behavioral therapy
The consumption of pan, betel nut, chillies, spices, & commercially available, pan masalas, guthkas with or without tobacco is increasing in India. So people should be encouraged to stop these habits
Affected patients should be explained about the disease and possible malignant potential of OSMF.
Possible irritants should be removed
Nutritional supplements.

61. Intralesional injections of hyaluronidase.
MEDICINAL THERAPY
Antioxidants
Intralesional injections of hyaluronidase.
Use of Placentrix 2ml solution at interval of 3 days in five divided region
Topical application of 4% Acetic acid (variable) 3 times daily.

62. Topical application of immunomodulators:
5 Fluorouracil
Systemic administration of immunomodulators
Levamisole 150mg for 3 weeks
Dapsone 75 mg O.D for 90 days

63. SURGICAL TREATMENT Fibrotomy Cryosurgery Laser treatment

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