ORAL SUBMUCOUS FIBROSIS- PPT
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Transcript of ORAL SUBMUCOUS FIBROSIS- PPT
Oral Submucous Fibrosis
Presented by:Dr Kalpajyoti Bhattacharjee
CONTENTS Introduction Definition Epidemiology Nomenclature Classification Etiopathogenesis Clinical features Histopathology Differential diagnosis Special investigations Malignant potential Treatment and Management
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.
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
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.
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
EPIDEMIOLOGYOral 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.
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
NOMENCLATURE
AUTHORS YEAR NOMENCLATURE GIVENSchwartz 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
CLASSIFICATION
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
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
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.
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
• 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.
etioPATHOGENESIS
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.
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).
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)
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.
Arecanut:
Four alkaloids- Arecoline, Arecaidine, Guvacine, Guvacoline.
Arecoline – main agent. (Tilakaratne 2006).
Flavanoid components- tannins and catechins.
Fibroblastic proliferation and inceased collagen formation.
Chronic placement of betel quid (areca nut)
Arecoline
Fibrosis
Rigidity & limited mouth opening
ROLE OF ARECOLINE
Arecoline
( Slaked lime) (Hydrolysis )
Arecaidine
Fibroblast stimulation & proliferation
Increased collagen synthesis
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
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.
Arecoline
Increased production of Tissue inhibitors of metalloproteinase (TIMP)
Inhibits activated collagenase
Increased production of collagen/decreased degradation of collagen
Arecoline altering p53, checkpoint kinase
G2/M cell cycle arrest
Supresses endothelial cell population
Atrophy of epithelium & hypoxic environment
carcinogenesis
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 stimulation & proliferation
Increased collagen synthesis
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
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)
ACCUMULATION OF COLLAGEN AND OTHER CHANGES IN ECM
Early stage – tenascin, fibronectin, perlecan and collagen type III
were enhanced in lamina propria and submucosa.
Intermediate stage – elastin extensively and irregularly deposited
around muscle fibres together with above mentioned molecules
Advanced stage – all the ECM molecules get decreased and
replaced by collagen type I
Heat shock protein (HSP 47) is a collagen specific molecular
chaperone involved in the processing and/or secretion of
procollagen. HSP 47 is significantly upregulated in OSF. Arecoline
was found to elevate HSP 47 expression in fibroblasts.
Cystatin C, a non glycosylated basic protein is increased in a
variety of fibrotic diseases, Cystatin C was found to be
upregulated both at m–RNA and protein levels in the disease.
Arecoline is responsible for this enhancement in a dose
dependent manner
EPITHELIAL MESENCHYMAL TRANSITION (EMT)
ANE caused cell injury
ROS
MAPK & NF kB pathways involved in EMT
Alteration of normal keratinocyte
morphology
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 underlying CT
Adaptive response of mucosa to cope up with the hypoxia caused by fibrosis
HYPOXIA
Extensive fibrosis
Reduction in vascularity
Hypoxia
atrophy & ulceration overexpression of HIF-1α
malignant transformation
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
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 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
Blanching seen over left buccal mucosa
Blanching seen on ventral surface of tongue, floor of mouth and restricted movements of tongue
Decreased mouth opening in oral submucous fibrosis patient
Soft palate and faucial pillars showing redness
Soft palate showing blanching and shrunken uvula seen inthe posterior part
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
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
Classical oral submucous fibrosis (OSMF) showing thin atrophic epithelium with chronic inflammation and dense fibrosis in the submucosa (hematoxylin-eosin, original magnification 200).
CONNECTIVE TISSUE CHANGES
Pindborg et al (1966) have described four consecutive stages in
submucous fibrosis cases based on sections stained with
haemotoxylin and eosin:
The changes are based on following criteria
Presence or absence of edema
Nature of the collagen bundles
Overall fibroblastic response
State of the blood vessels
Predominant cell type in the inflammatory exudates
Very early stage
Fine fibrillar collagen dispersed with marked edema and
strong fibroblastic response showing plump young fibroblasts
containing abundant cytoplasm will be observed.
Blood vessels - occasionally normal, but more often they are
dilated and congested.
Inflammatory cells- polymorphonuclear leukocytes with
occasional eosinophils, are present.
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.
Histopathological picture showing early changes in the oral submucous fibrosis
Moderately advanced stage
In this stage, the collagen is moderately hyalinised.
The amorphous change starts from the juxta-epithelial basement
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.
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.
Histopathological picture of advanced stage oral submucous fibrosis showing atrophied epithelium, increased fibrosis and hyalinization of submucosal tissues
Khanna and Andrade (1995); grouped OSMF features into 4 groups based on histopathological features:
Group I : Very early changes Common symptom is burning sensation in the mouth. Acute ulceration and recurrent stomatitis Not associated with mouth opening limitation.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.
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.
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
Inflammatory exudates consists mainly of lymphocytes Epithelium markedly atrophic with loss of rete pegs Muscle fibers seen interspersed with thickened and dense
collagen fibers.
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.
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
(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 MARKERSHeat shock proteins 47
Cystatin c
Survivin
Endothelial markers- CD31,
CD34, CD105
Basic fibroblastic growth factor
P53
Bcl-2
Ki-67
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 growing squamous cell carcinoma in one third of the patients with the disease.
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 patients2. Higher incidence of squamous cell carcinoma in patients with
OSF3. Histological diagnosis of cancer without any clinical suspicion
in OSF4. High frequency of epithelial dysplasia &5. Higher prevalence of leukoplakia among OSF.
Malignant transformation rate of OSF was found to be in the range of 7–13% (Tilakaratne 2006).
According to long-term follow-up studies a transformation rate of 7.6% over a period of 17 years was reported (Murti1985).
BIOLOGICAL STUDIES
Blood chemistry and haematological variations.
Iron, vitamin B12, folate levels
ESR, anemia and eosinophilia, gammaglobulin
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.
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
5) Nutritional support: High proteins, calories, vitamin B complex, other vitamins and minerals.
6) Physiotherapy: forceful mouth openings, heat therapy.
7) Surgical treatment: cutting the fibrotic bands resulted in more fibrosis and disability.
Excision of fibrotic tissues and covering the defect with split thickness skin, fresh human amnion or buccal fat pad (BFP) grafts have been applied to treat OSMF
8) Stem cell therapy Recently scientists have proven that intralesional injection
of autologous bone marrow stem cells is a safe and effective treatment modality in oral sub mucosal fibrosis.
Autologous bone marrow stem cell injections induces angiogenesis in the area of lesion which in turn decreases the extent of fibrosis thereby leading to significant increase in mouth opening
Possible therapeutic interventions for OSF
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.
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
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
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