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Oral SubmucOuS
FibrOSiS
Presented by:
Dr Kalpajyoti Bhattacharjee
CONTENTS
 Introduction
 Definition
 Epidemiology
 Nomenclature
 Classification
 Etiopathogenesis
 Clinical features...
INTRODUCTION
 Oral mucous membrane is a unique area of the body, which
is continuously exposed to various kinds of stress...
 One such reaction of the collagen of oral mucosa to arecanut
is oral submucous fibrosis.
 Oral Submucous Fibrosis (OSMF...
 First described by Schwartz “atrophica idiopathic mucosae
oris” in 1952 among 5 Indian females in Kenya.
 1953- Joshi f...
 Most widely accepted definition by Pindborg JJ & Sirsat S.M (1966)
states-
“OSMF is an insidious chronic disease affecti...
EPIDEMIOLOGY
Oral submucous fibrosis (OSF), first described in the early 1950s, is
a potentially malignant disease predom...
 The condition was first described in ancient Indian Manuscripts
by Sushruta describing it as “VEDARI” where he describes...
NOMENCLATURE
AUTHORS YEAR NOMENCLATURE GIVEN
Schwartz 1952 Atrophia Idiopathica mucosa oris
Joshi 1953 Submucosa fibrosis ...
claSSiFicaTiO
N
Based on clinical findings
Pindborg JJ 1989
Stage I- Stomatitis; erythematous mucosa, vesicles,
ulcers, petechiae
Stage ...
Lai DR 1995
Based on interincisal distance
Group 1- >35mm
Group 2- between 30 and 35mm
Group 3- between 20 and 30mm
Gr...
13
Haider SM (2000)
Clinical stage:
Stage I: faucial bands only
StageII: faucial and buccal bands
Stage III: Faucial, bucc...
Prakash R. et al
Based on morphologic variants of soft palate
Type 1: Leaf shaped
Type 2: Rat tail shaped
Type 3: Butt sha...
15
• Grade I : Epithelium shows Hyperkeratosis, intra cellular
edema, little basal cell hyperplasia, rete ridges present.
...
eTiOPaTHOGeNeS
iS
ETIOLOGY
 Multifactorial
 Local factors:
Chillies and
Arecanut
 Systemic factors :
Nutritional deficiency,
Genetic pred...
Chillies-
 Capsaicin, an active principle, mild irritant, which brings about
epithelial and connective tissue changes in ...
 Mutogenic and enhance the tumorigenicity of tobacco in
experimental animals. (Bhide 1992)
 Increases the risk of cancer...
Nutritional deficiencies
May be secondary
OSMF patients cannot tolerate spicy food & the opening of
the mouth in OSF patie...
Arecanut:
 Four alkaloids- Arecoline, Arecaidine, Guvacine, Guvacoline.
Arecoline – main agent. (Tilakaratne 2006).
 Fla...
Chronic placement of betel quid (areca nut)
Arecoline
Fibrosis
Rigidity & limited mouth opening
ROLE OF ARECOLINE
Arecoline
( Slaked lime) (Hydrolysis )
Arecaidine
Fibroblast stimulation & proliferation
Increased colla...
Large quantity of tannin present in areca nut
Inhibits collagenases
Reduced collagen degradation
Stabilization of collagen...
Arecoline
Increased generation of ROS
(oxidative stress)
Activates various transcription factors
( NF kappa B, JNK & p38 M...
Arecoline
Increased production of Tissue inhibitors of
metalloproteinase (TIMP)
Inhibits activated collagenase
Increased p...
Arecoline
altering
p53, checkpoint kinase
G2/M cell cycle arrest
Supresses endothelial cell population
Atrophy of epitheli...
Arecoline + keratinocytes
differentiation
Fibroblast myofibroblast
ECM contraction
fibrosis
Presence of Copper in nut:
Copper content in areca nut
( Increased activity of lysyl
oxidase enzyme )
Fibroblast stimulati...
MATRIX METALLOPROTEINASES AND TISSUE
INHIBITORS OF MATRIX METALLOPROTEINASES
Arecoline
Increased ROS and DNA double strand...
Fibrogenic cytokines
External stimuli
Increased levels of cytokines in the lamina
propria
Induce development of disease
TG...
ACCUMULATION OF COLLAGEN AND
OTHER CHANGES IN ECM
 Early stage – tenascin, fibronectin, perlecan and collagen type III
we...
 Heat shock protein (HSP 47) is a collagen specific molecular
chaperone involved in the processing and/or secretion of
pr...
EPITHELIAL MESENCHYMAL TRANSITION (EMT)
ANE caused cell injury
ROS
MAPK & NF kB pathways involved in EMT
Alteration of nor...
 Keratinocytes PGE2, IL-6, TNFα and TGFβ
fibrosis
GROWTH FACTORS AND INFLAMMATORY
CYTOKINES
ANGIOGENESIS RELATED MOLECULES
Overexpression of iNOS, b-FGF, TGF-β, PDGF, HIF-1α
(increased MVD)
Maintain vascularity of ...
HYPOXIA
Extensive fibrosis
Reduction in vascularity
Hypoxia
atrophy & ulceration overexpression of HIF-1α
malignant transf...
ALTERATIONS OF CELL CYCLE
 PCNA index is higher in OSF epithelium than normal oral mucosa
– increased malignant transform...
GENETIC SUSCEPTIBILITY
Genomic instability (LOH)
Absence of tumor suppressor genes
Malignant transformation of OSF
CLINICAL FEATURES
EARLY OSMF ADVANCED OSMF
Burning sensation
Blisters
Ulcerations
Excessive salivation
Defective gustatory...
Blanching seen over left
buccal mucosa
Blanching seen on
ventral surface of
tongue, floor of
mouth and restricted
movement...
Decreased mouth
opening in oral
submucous fibrosis
patient
Soft palate and
faucial pillars
showing redness
Soft palate showing
blanching and
shrunken uvula seen in
the posterior part
Histopathology
 Histological findings in OSMF cases were found to vary depending
on the clinical severity of the cases an...
 The atrophic epithelium also exhibits intracellular edema, signet
cells and epithelial atypia (focal dysplasia).
 Epith...
Classical oral submucous fibrosis (OSMF) showing thin atrophic
epithelium with chronic inflammation and dense fibrosis in ...
CONNECTIVE TISSUE CHANGES
 Pindborg et al (1966) have described four consecutive stages in
submucous fibrosis cases based...
Very early stage
 Fine fibrillar collagen dispersed with marked edema and
strong fibroblastic response showing plump youn...
Early stage
 In this stage juxta-epithelial area shows early hyalinization.
 The collagen is still seen as separate bund...
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 j...
Advanced stage
 The collagen is completely hyalinised and is seen as a
smooth sheet with no distinct bundles or edema
 H...
Histopathological picture of advanced stage oral submucous
fibrosis showing atrophied epithelium, increased fibrosis and
h...
Khanna and Andrade (1995); grouped OSMF features into 4
groups based on histopathological features:
Group I : Very early c...
Group II : Early cases
 Buccal mucosa appears mottled and marble-like
 Widespread sheets of fibrosis palpable
 Patients...
Group III : Moderately advanced cases
 Trismus evident with an interincisal distance of 15-25mm
 Buccal mucosa appears p...
 Inflammatory exudates consists mainly of lymphocytes
 Epithelium markedly atrophic with loss of rete pegs
 Muscle fibe...
Group IV A : Advanced cases:
 Trismus is severe with interincisal distance of less than 15mm
 The fauces are thickened, ...
Histology:
 Collagen hyalinized as smooth sheet.
 Extensive fibrosis obliterating the mucosal blood vessels and
eliminat...
(a) Loss of striation in muscle; (b) Floculant material
showing degeneration
OSMF showing extensive fibrosis in the submucosa
(hematoxylin-eosin, original magnification 200).
OSMF with lichenoid reaction, showing bandlike
inflammatory exudate with fibrosis (hematoxylin-
eosin).
SPECIAL INVESTIGATIONS
SPECIAL STAINS
Van Gieson's Stain
Masson's trichrome
stain
Picrosirius red
IHC MARKERS
Heat sho...
DIFFERENTIAL DIAGNOSIS
 Scleroderma
 Fibroma
 Generalized fibromatosis
 Anemia
 Amyloidosis
MALIGNANT POTENTIAL
 The precancerous nature of OSF was first discovered by
Paymaster (1956), when he observed slow growi...
 This was confirmed with various groups & Pindborg (1972)
put forward five criteria to prove that the disease is
precance...
 Malignant transformation rate of OSF was found to be in the
range of 7–13% (Tilakaratne 2006).
 According to long-term ...
BIOLOGICAL STUDIES
Blood chemistry and haematological variations.
Iron, vitamin B12, folate levels
ESR, anemia and eosinop...
TREATMENT
1) Restriction of habits:
Reduction or elimination of habit of areca nut chewing is an
important preventive meas...
3) Hyaluronidase:
Break down hyaluronic acid, lower the viscosity of the
intercellular cement substance and also decreases...
5) Nutritional support: High proteins, calories, vitamin B complex,
other vitamins and minerals.
6) Physiotherapy: forcefu...
8) Stem cell therapy
Recently scientists have proven that intralesional injection
of autologous bone marrow stem cells is ...
Possible therapeutic interventions for OSF
CONCLUSION
 In summary, the available literature indicates that the main
aetiological factors for OSF are the constituent...
REFERENCES
 Neville B W, Damm D D, Allen C M, Bouquot J E. Oral &
maxillofacial pathology; elsevier ,noida,2nd
ed.
 Raje...
 Oral Submucous Fibrosis: Review on Mechanisms of
Pathogenesis and Malignant Transformation, Rasika
Priyadharshani Ekanay...
THANK
YOU
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  1. 1. Oral SubmucOuS FibrOSiS Presented by: Dr Kalpajyoti Bhattacharjee
  2. 2. CONTENTS  Introduction  Definition  Epidemiology  Nomenclature  Classification  Etiopathogenesis  Clinical features  Histopathology  Differential diagnosis  Special investigations  Malignant potential  Treatment and Management
  3. 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. 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 juxta-epithelial inflammatory reaction along with mucosal fibrosis.  OSMF is characterized by deposition of dense collagen in the connective tissue
  5. 5.  First described by Schwartz “atrophica idiopathic mucosae oris” in 1952 among 5 Indian females in Kenya.  1953- Joshi from Bombay redesignated the condition as Submucous Fibrosis.
  6. 6.  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
  7. 7. 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. 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.
  8. 8.  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
  9. 9. 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 De sa 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
  10. 10. claSSiFicaTiO N
  11. 11. Based on clinical findings Pindborg JJ 1989 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
  12. 12. 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
  13. 13. 13 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.
  14. 14. 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
  15. 15. 15 • 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.
  16. 16. eTiOPaTHOGeNeS iS
  17. 17. 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.
  18. 18. 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. (Sirsat & Khanolkar 1960).
  19. 19.  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)
  20. 20. 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.
  21. 21. Arecanut:  Four alkaloids- Arecoline, Arecaidine, Guvacine, Guvacoline. Arecoline – main agent. (Tilakaratne 2006).  Flavanoid components- tannins and catechins.  Fibroblastic proliferation and inceased collagen formation.
  22. 22. Chronic placement of betel quid (areca nut) Arecoline Fibrosis Rigidity & limited mouth opening
  23. 23. ROLE OF ARECOLINE Arecoline ( Slaked lime) (Hydrolysis ) Arecaidine Fibroblast stimulation & proliferation Increased collagen synthesis
  24. 24. Large quantity of tannin present in areca nut Inhibits collagenases Reduced collagen degradation Stabilization of collagen by tannins (and catachins polyphenols) Arecoline + tannin → ↓ degradation of collagen ↑ production of collagen
  25. 25. 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.
  26. 26. Arecoline Increased production of Tissue inhibitors of metalloproteinase (TIMP) Inhibits activated collagenase Increased production of collagen/decreased degradation of collagen
  27. 27. Arecoline altering p53, checkpoint kinase G2/M cell cycle arrest Supresses endothelial cell population Atrophy of epithelium & hypoxic environment carcinogenesis
  28. 28. Arecoline + keratinocytes differentiation Fibroblast myofibroblast ECM contraction fibrosis
  29. 29. Presence of Copper in nut: Copper content in areca nut ( Increased activity of lysyl oxidase enzyme ) Fibroblast stimulation & proliferation Increased collagen synthesis
  30. 30. 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
  31. 31. Fibrogenic cytokines External stimuli Increased levels of cytokines in the lamina propria Induce development of disease TGF-ß Platelet derived growth factor (PDGF) Basic fibroblast growth factor (bFGF)
  32. 32. 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
  33. 33.  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
  34. 34. EPITHELIAL MESENCHYMAL TRANSITION (EMT) ANE caused cell injury ROS MAPK & NF kB pathways involved in EMT Alteration of normal keratinocyte morphology
  35. 35.  Keratinocytes PGE2, IL-6, TNFα and TGFβ fibrosis
  36. 36. GROWTH FACTORS AND INFLAMMATORY CYTOKINES
  37. 37. ANGIOGENESIS RELATED MOLECULES Overexpression of iNOS, b-FGF, TGF-β, PDGF, HIF-1α (increased MVD) Maintain vascularity of underlying CT Adaptive response of mucosa to cope up with the hypoxia caused by fibrosis
  38. 38. HYPOXIA Extensive fibrosis Reduction in vascularity Hypoxia atrophy & ulceration overexpression of HIF-1α malignant transformation
  39. 39. 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
  40. 40. GENETIC SUSCEPTIBILITY Genomic instability (LOH) Absence of tumor suppressor genes Malignant transformation of OSF
  41. 41. 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
  42. 42. Blanching seen over left buccal mucosa Blanching seen on ventral surface of tongue, floor of mouth and restricted movements of tongue
  43. 43. Decreased mouth opening in oral submucous fibrosis patient Soft palate and faucial pillars showing redness
  44. 44. Soft palate showing blanching and shrunken uvula seen in the posterior part
  45. 45. 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
  46. 46.  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
  47. 47. Classical oral submucous fibrosis (OSMF) showing thin atrophic epithelium with chronic inflammation and dense fibrosis in the submucosa (hematoxylin-eosin, original magnification 200).
  48. 48. 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
  49. 49. 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.
  50. 50. Early stage  In this stage juxta-epithelial area shows early hyalinization.  The collagen is still seen as separate bundles which are thickened.  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.
  51. 51. Histopathological picture showing early changes in the oral submucous fibrosis
  52. 52. 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.
  53. 53. 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.
  54. 54. Histopathological picture of advanced stage oral submucous fibrosis showing atrophied epithelium, increased fibrosis and hyalinization of submucosal tissues
  55. 55. 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.
  56. 56. 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.
  57. 57. 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
  58. 58.  Inflammatory exudates consists mainly of lymphocytes  Epithelium markedly atrophic with loss of rete pegs  Muscle fibers seen interspersed with thickened and dense collagen fibers.
  59. 59. 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.
  60. 60. 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
  61. 61. (a) Loss of striation in muscle; (b) Floculant material showing degeneration
  62. 62. OSMF showing extensive fibrosis in the submucosa (hematoxylin-eosin, original magnification 200).
  63. 63. OSMF with lichenoid reaction, showing bandlike inflammatory exudate with fibrosis (hematoxylin- eosin).
  64. 64. 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
  65. 65. DIFFERENTIAL DIAGNOSIS  Scleroderma  Fibroma  Generalized fibromatosis  Anemia  Amyloidosis
  66. 66. 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.
  67. 67.  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.
  68. 68.  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).
  69. 69. BIOLOGICAL STUDIES Blood chemistry and haematological variations. Iron, vitamin B12, folate levels ESR, anemia and eosinophilia, gammaglobulin
  70. 70. 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.
  71. 71. 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
  72. 72. 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
  73. 73. 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
  74. 74. Possible therapeutic interventions for OSF
  75. 75. 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.
  76. 76. REFERENCES  Neville B W, Damm D D, Allen C M, Bouquot J E. Oral & maxillofacial pathology; elsevier ,noida,2nd ed.  Rajendran R & Shivapathasundaram B. Shafer’s textbook of oral pathology; Elsevier, Noida, 6th ed.  Oral Submucous Fibrosis - A review [Part 2], Dr. Savita JK* Dr. Girish HC** Dr. Sanjay Murgod Dr. Harish Kumar, , Journal of Health Sciences and Research, Volume 1, Number 2, August – 2010  Oral Submucous Fibrosis - A review [Part 2], Dr. Savita JK* Dr. Girish HC** Dr. Sanjay Murgod Dr. Harish Kumar, Journal of Health Sciences and Research, Volume 2, Number 1, April – 2011  CLASSIFICATION SYSTEMS FOR ORAL SUBMUCOUS FIBROSIS- FROM PAST TO PRESENT: A REVIEW, Vikas Berwal et al, International Journal of Dental and Health Sciences Volume 01,Issue 06
  77. 77.  Oral Submucous Fibrosis: Review on Mechanisms of Pathogenesis and Malignant Transformation, Rasika Priyadharshani Ekanayaka and Wanninayake Mudiyanselage Tilakaratne, J Carcinogene Mutagene S5: 002. doi:10.4172/2157-2518.S5-002.  Oral submucous fibrosis: etiology, pathogenesis, and future research, R. Rajendran, Bulletin of the World Health Organization, 1994, 72 (6): 985-996  A prospective transmission electron microscopic study of muscle status in oral submucous fibrosis along with retrospective analysis of 80 cases of oral submucous fibrosis, Sumathi MK, Narayanan Balaji, Malathi Narasimhan, Journal of Oral and Maxillofacial Pathology Vol. 16 Issue 3 Sep - Dec 2012  Histochemical analysis of polarizing colors of collagen using Picrosirius Red staining in oral submucous fibrosis, Surekha Velidandla ey al, Journal of International Oral Health 2014; 6(1):33-38
  78. 78. THANK YOU

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