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Review Article

Oral submucous fibrosis- A review [part 2]


Dr Savita JK*, Dr Girish HC**, Dr Sanjay Murgod , Dr Harish Kumar

Abstract Histopathology
One of the most common precancerous conditions which Structural changes in oral submucous fibrosis have been studied in detail both
are widely prevalent in the Indian subcontinent is Oral at the light and electron microscopic levels. Reichart et al. (1984) and Van Wyk
Submucous Fibrosis. This is an attempt to review the
various aspects of the condition and to understand the
et al. (1990) studied the patterns of distribution of different types of collagen in
disease better. This better understanding may be of use in subjects with confirmed oral submucous fibrosis. Ultrastructural findings of
initiating improved therapies and also aid in the prognosis muscle degeneration in oral submucous fibrosis were reported by Cannif
of the condition. (1985).44,45
Keywords : Oral submucous fibrosis, etiopathogenesis

Epithelial Changes
*Senior Lecturer, **Professor & HOD, Professor,
RajaRajeswari Dental College and Hospital. Histological findings in OSMF cases were found to vary depending on the
Bangalore. 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
Reader, Department of Oral Pathology, normal to atrophic and hyperplastic epithelium (Sirsat & Khanolkar, 1957).
Kalinga Inst. Of Dental Sciences, Patia, Bhuvaneshwar 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
Correspondence: Dr Sanjay Murgod, Professor oral mucosa. The atrophic epithelium also exhibits intracellular edema, signet
RajaRajeswari Dental College and Hospital,
cells and epithelial atypia (focal dysplasia). Epithelial keratinization, especially
Kumbalgodu, Mysore Road, Bangalore - 560074.
Email id: savijangal@hotmail.com
the tendency of atrophic and hyperplastic epithelium to show keratinization
was higher when compared to normal. Vacuolization of prickle cell layer,
increased mitotic activities were evident in a small number of cases.46

Connective tissue changes


Characteristically the changes begin in connective tissue and vary with
different stages of OSMF. 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.37

Very early stage


In this stage, fine fibrillar collagen dispersed with marked edema and strong
fibroblastic response showing plump young fibroblasts containing abundant
cytoplasm will be observed (Fig 8). The blood vessels are occasionally normal,
but more often they are dilated and congested. Inflammatory cells, mainly
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.

Moderately advanced stage


In this stage, the collagen is moderately hyalinised. The amorphous change
starts from the juxta-epithelial basement membrane (Fig 9). Occasionally,
thickened collagen bundles are still seen separated by slight residual edema.

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Review Article

The adult fibroblastic cells have elongated spindle shaped nuclei Histology
and scanty cytoplasm. Blood vessels are either normal or Juxtaepithelial hyalinization present
constricted as a result of increased surrounding tissue. The Collagen present as thickened but separate bundles.
inflammatory exudate consists of lymphocytes, plasma cells and Blood vessels dilated and congested
occasional eosinophils. Young fibroblasts seen in moderate number
Inflammatory cells mainly consist of polymorphonuclear
leukocytes with few eosinophils and occasional plasma cells.
Advanced stage
Flattening or shortening of epithelial rete pegs evident with
Here, the collagen is completely hyalinised and is seen as a varying degree of keratinization.
smooth sheet with no distinct bundles or edema (Fig 10). The
hyalinised connective tissue becomes hypocellular with thin Group III : Moderately advanced cases
elongated cells with vestigial nucleus at rare intervals along the
Trismus evident with an interincisal distance of 15-25mm
bundles. Blood vessels are completely obliterated or narrowed.
Buccal mucosa appears pale and firmly attached to
The inflammatory exudate consists of lymphocytes and plasma
underlying tissues
cells and occasional eosinophils. Interestingly the melanin-
Atrophy of vermilion border
containing cells in the lamina propria are surrounded by dense
Vertical fibrous bands palpable at the soft palate,
collagen, which explains the clinically observed loss of
pterygomandibular raphe and anterior faucial pillars.
pigmentation.15,43
Histology
Tilakaratne (2005) modified above said pindborg's stages: Juxtaepithelial hyalinization present
Early stage : Large number of lymphocytes in subepithelial, Thickened collagen bundles faintly discernible, separate by
connective tissue zone along with myxoedematous changes. very slight, residual edema.
Intermediate stage : Granulation changes close to the muscle Blood vessels, mostly constricted
layer and hyalinization appears in subepithelial zone where Mature fibroblasts with scanty cytoplasm and spindle-
blood vessels are compressed by fibrous bundles. Reduced shaped nuclei
inflammatory cells in subepithelial layer. Inflammatory exudates consists mainly of lymphocytes
Advanced stage: Inflammatory cell infiltrate is hardly seen. Epithelium markedly atrophic with loss of rete pegs
Number of blood vessels dramatically small in subepithelial Muscle fibers seen interspersed with thickened and dense
zone. Marked fibrosis areas with hyaline changes extending collagen fibers.
from subepithelial to superficial muscle layers. Atrophic,
degenerative changes start in muscle fibers.43 Group IV A : Advanced cases
Trismus is severe with interincisal distance of less than 15mm
Khanna and Andrade (1995); grouped OSMF features into 4 The fauces are thickened, shortened and firm on palpation.
groups based on histopathological features. Uvula is shrunken and appears as a small, fibrous bud
Group I : Very early changes Tongue movements are limited
Common symptom is burning sensation in the mouth. On palpation of lips, circular band felt around entire mouth.
Acute ulceration and recurrent stomatitis Group IV B: Advanced cases with premalignant and
Not associated with mouth opening limitation. malignant changes.
Histology Hyperkeratosis, leukoplakia, or squamous cell carcinoma can
Fine fibrillar collagen network interspersed with marked be seen.
edema. Histology
Blood vessels dilated and congested.
Collagen hyalinized as smooth sheet.
Large aggregate of plump, young fibroblasts present with
Extensive fibrosis obliterating the mucosal blood vessels and
abundant cytoplasm.
eliminating the melanocytes.
Inflammatory cells mainly consist of polymorphonuclear
Fibroblasts markedly absent within the hyalinized zones.
leukocytes with few eosinophils.
Total loss of epithelial rete pegs.
Epithelium normal.
Mild to moderate atypia present.
Group II : Early cases Extensive degeneration of muscle fibers evident.43
Buccal mucosa appears mottled and marble-like
Widespread sheets of fibrosis palpable
Patients with an interincisal distance of 26-35mm

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Review Article

Relevance of epithelial-mesenchymal interaction patients may be due to genotoxic effect of the constituents of
in oral submucous fibrosis. betel quid. 2

The epithelium depends on connective tissue for nutrient supply, Mast cell
with changes such as inflammation in the connective tissue; the
epithelial cells seem to respond in a characteristic manner. As we Among the cellular elements in the connective tissue mast cells
know, the pathogenic mechanism in oral submucous fibrosis are commonly present. They contain coarse granules of
starts in the connective tissue, the epithelium responding histamine in the cytoplasm, which are responsible for the
secondarily to it, a persistent juxtaepithelial inflammatory itching sensation in early stages observed in some patients. The
response is characteristic feature. Hyperplastic epithelial release of mast cell granules may initiate a change in the
responses seen in early and advanced stages are due to local connective tissue ground substance by changing the
irritants to protect underlying tissues. This hyperplastic intracellular fluid or free tissue water into a mucinous fluid. In
epithelium show increased permeability to water. This reduced normal buccal mucosa the mast cells ranged between 0-5,
barrier function may be related to an increased widening of the while in OSF the number varied between 2-9 cells per
intercellular space and an increased turnover rate of this tissue.47 microscopic field in various grades.42

Serum-derived antibodies provide a further basis for an increase Electron microscopy


in mucosal permeability. Although serum derived IgG retards the
penetration of its corresponding antigen, it cannot cause Study of oral submucous fibrosis by SEM revealed that there is
impairment of the mucosal barrier through immune complex significant obliteration of the elevated ridges of the cell
formation or an increased absorption of antigen into epithelial boundaries, while the microrugae were almost unaltered.
cells.2 Many cases showed desquamation of squamous epithelial
cells, while other studies showed complete focal loss of the
Thus the epithelial response in oral submucous fibrosis is covering epithelium and exposing subepithelial connective
secondary to progressive changes in the connective tissue. The tissue. The striking feature in this study was the presence of
hyperplastic epithelial response and atrophy reduces the barrier microbes on the epithelial cell surface with invasion to the
function of the mucosa to local irritants. Circulating immune exposed sub-epithelial connective tissue, resulting in altered
complexes and serum antibodies in oral submucous fibrosis oral homeostasis, which in turn helps in proliferation of oral
probably help to accentuate the already existing pathological microbes. Examination of oral submucous fibrosis cases with
change in the oral mucosa.2 naked eye showed the presence of multiple, discrete pin-
headed erythematous areas which could be the areas of
Biological studies on individuals and tissues from complete focal loss of the surface epithelium as revealed by this
study (Paul 1995).15,48
cases of oral submucous fibrosis.
Blood chemistry and haematological variations. Ultra structurally the layers of cells will be reduced in number
The deficiency of iron, vitamin B12 and folate can affect the with intracellular edema resulting in loosened interdigitation
integrity of the oral mucosa. Significant haematological and widened intercellular space. The cell organelles and
abnormalities are reported in oral submucous fibrosis including, tonofilaments are reduced in number. Some cells appeared
increased ESR, anemia and eosinophilia (Pindborg 1966), darker with shrunken cytoplasm, reduced or absent cell
increased gammaglobulin, decrease in serum iron and increase in organelle and pyknotic nuclei with marginated chromatin.
total iron binding capacity. Thus iron deficiency anemia appears
to be one of the causes and not the effect of the disorder.2 Lamina propria-The collagen in oral submucous fibrosis are
reported as normally banded (sirsat & khanolkar 1987). Several
histological and electron-microscopic studies reported that the
Cytogenetics collagen itself is abnormal. It shows hyaline degeneration,
Chromosomal instability has long been associated with the fragmentation, elastic degeneration (Sirsat & Pindborg 1967)
neoplastic process and the quantitative assay of sister chromatid and changed staining properties. The ultrastructural features
exchange provides an easy, rapid and sensitive method for were described as abnormal collagen fibrils, fragmented and
studying chromosome/DNA instability and its subsequent repair bent at odd angles. Some fibers showed frayed ends, with
processes. A study (Gosh 1990) is done to investigate sister apparent partial degeneration into amorphous material (sirsat
chromatid exchange levels in the peripheral blood of patients & khanolkar 1957) an excess of fine (immature) fibrils without
with oral submucous fibrosis and to correlate them with the habit true bundle formation and marked variation of diameter of the
of different forms of tobacco/areca nut usage. The increase in fibrils (Reichart 1984).49
frequencies of sister chromatid exchange observed with OSF

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Binnie & Cawson (1972) studied one case and concluded that the grayish pink, rather than the customary deep red when stained
fine fibrils are probably embryonic collagen and the defect lies in by these methods.52
the polymerization and maturation. In contrast to above studies,
Fullmer (1966) reported that out of 20 specimens of OSF, one As submucous fibrosis reaches a more advanced stage, much of
showed altered staining behavior for collagen and elastic fibers.50 the connective tissue appears hyalinized without discernible
collagen bundles.
Wyk (1990) study showed, adjacent to the basement membrane
there was a thin zone relatively sparsely populated with Afroz, (2006) study showed thinned out mucosa and thickened
individual collagen fibrils and loosely arranged groups of fibrils avascular subepithelial connective tissue in most of the cases.
running parallel to the epithelial-connective tissue junction. With the use of Van Gieson's Stain, features similar to the
Some fibrils lacked the typical periodicity of collagen and a similar findings of Hanner et al (1971) are seen. 53
pattern was seen in submucosa next to salivary glands and
muscle bundles. Deeper in the lamina propria the collagen Haque (1997) investigated the presence and distribution of
consisted of thick, dense bundles arranged in regular, interwoven inflammatory cells and MHC class II antigen expression by
pattern. Another evident feature is, dense collagen (Type III) epithelial and immunocompetent cells using a three-stage
bundles surrounding a capillary wall and lying in close proximity immunoperoxidase method on frozen sections. The cell
to endothelial cells.49 populations detected in OSF showed higher numbers of CD3
and HL.A-DR-positive cells compared with those of the normal
Cannif (1988) reported degenerative changes in muscle fibers are tissues. The pattern of staining for CD4-positive cells in OSF
more pronounced among individuals with restricted mouth tissues was similar to that of CD3-positive cells both in the
opening. In between the collagen bundles spindle shaped cells epithelium and connective tissue and was higher than that in
with elongated nuclei were seen; these cells lack basal lamina and normal tissues. A few scattered CD8- positive cells and only
have very prominent, extensive rough endoplasmic reticulum occasional CD20- and CD68-positive cells were seen in OSF
and were identified as fibroblasts.48 sections. Few CD45RA-positive cells were found in the
epithelium and lamina propria of OSF sections. However, OSF
Lenhatjer & Bayreuther (1986) described three distinct fibroblast specimens showed high numbers of HLADR- positive cells in the
cell forms in rat connective tissue that can be identified on the basal layer of the epithelium, juxtaepithelium and in the lamina
basis of their morphology. They can also be distinguished from propria in a similar distribution to that of CD3 cells compared
one another by the amount and type of collagen synthesized. The with the normal tissues. Most HLA-DR-positive cells in the
F1 fibroblast is spindle-shaped, highly proliferative and secretes epithelium showed dendrites directed vertically towards the
low levels of type I and III collagen. F2 is more epithelioid, less surface. The increased evidence of CD4 and HLA-DR positive
proliferative and synthesizes relatively more collagen, while F3, cells in OSF tissues suggests that most lymphocytes were
large stellate cell and the least proliferative, produces four to activated and shows an increased presence of Langerhans'
eight times more type I and III collagen than F1. According to cells. The presence of these immunocompetent cells and high
these workers, F2 cells sequentially arise from Fl cells and that F3 ratio of CD4 to CD8 in OSF tissues suggest an ongoing cellular
cells sequentially arise from F2 cells. They found no evidence that immune response leading to a possible imbalance of
this process can be reversed.51 immunoregulation and alteration in local tissue architecture.54

Electron microscopy Reichart (1994) studied the distribution of procollagen type III,
collagen type VI and tenascin in confirmed oral submucous
Hanner 1971 found a definite alteration in the tinctorial quality of
fibrosis (OSF) using the immunogold-silver staining technique.
the connective tissues elements of OSMF when stained by the
Immunohistochemistry revealed a loss of stainable procollagen
Rinehart and Van Gieson methods. The covering epithelium was
type III and collagen type VI in the fibrotic zones of oral
atrophic and had atypical features with juxtaepithelial deposition
submucous fibrosis compared to normal oral mucosa. Tenascin
of abnormal material. This amorphous material stained atypically
was noted only very faintly at the subepithelial basement
with specific collagen stains in each instance. The most
membrane. This study showed that procollagen type III and
interesting feature was an amorphous change in the connective
collagen type VI in OSF were expressed in a specific pattern,
tissues, commencing downward from the epithelial basement
which allows a clear differentiation between fibrotic areas and
membrane. With H&E staining, this characteristic appeared as a
adjacent apparently normal connective tissue stroma. Loss of
peculiar eosinophilic band. The Rinehart and van Gieson stains
procollagen type III, and therefore a probable predominance of
showed this in a striking fashion. In contrast to the collagen in
collagen type I in collagen fiber bundles, and an almost
normal buccal mucosa, which exhibits an undulated bundled
complete loss of collagen type VI might explain the stiffness of
pattern the juxtaepithelial connective tissue band present in
t h e o r a l m u c o s a i n p a t i e n t s w i t h O S F. T h e
submucous fibrosis was quite amorphous and stained a faint
immunohistochemical findings provided evidence that the

1 Journal of Health Sciences and Research, Volume 2, Number 1, April - 2011


Review Article

process of fibrosis starts in the deeper subepithelial connective The concept of predisposition, which may precede other stages
tissue stroma and not close to the subepithelial basement (initiation and promotional stages) of carcinoma, comprises a
membrane.55 state in which the tissue shows increased susceptibility to the
action of the initiator, such as chemical carcinogen (Macdonald
Polarization colors of various purified collagens were studied 1975). The concept of predisposition accounts for the
(Dayan1989) in fibers of related thickness. Three different soluble pathogenesis of oral cancer in the development of OSF. It has
collagens of type I, insoluble collagen type I, lathyritic collagen been suggested that the atrophic epithelium in OSF is probably
type I, two p-N-collagens type I, pepsin extract collagen type II, more susceptible to the carcinogenic component which is often
two soluble collagens type III, p-N-collagen type III, and soluble present in tobacco used in India.16
collagen type V were submitted to a routine histopathologic
procedure of fixation, preparation of 5-microns-thick sections, The precancerous nature of OSF was first discovered by
staining with Picrosirius red and examination under crossed Paymaster (1956), when he observed slow growing squamous
polars. Polarization colors were determined for thin fibers (0.8 cell carcinoma in one third of the patients with the disease. This
micron or less) and thick fibers, (1.6-2.4 microns). Most thin fibers was confirmed with various groups & Pindborg (1972) put
of collagens and p-N-collagens showed green to yellowish-green forward five criteria to prove that the disease is precancerous.
polarization colors with no marked differences between the They included
various samples. Thick fibers of all p-N-collagens, lathyritic and High occurrence of OSF in oral cancer patients
normal 0.15 M NaCl-soluble collagens showed green to greenish- Higher incidence of squamous cell carcinoma in patients
yellow polarization colors, while in all other collagens, with OSF
polarization colors of longer wavelengths (from yellowish-orange Histological diagnosis of cancer without any clinical suspicion
to red) were observed. These data suggested that fiber thickness in OSF
was not the only factor involved in determining the polarization High frequency of epithelial dysplasia &
colors of Picrosirius red-stained collagens. Tightly packed and Higher prevalence of leukoplakia among OSF.
presumably, better aligned collagen molecules showed
polarization colors of longer wavelengths. Thus, packing of Most of the earlier studies (Pindborg 1967, Murti 1985, Lee
collagen molecules and not only fiber thickness plays a role in the 2003) have focused on the prevalence of epithelial dysphasia in
pattern of polarization colors of Picrosirius red-stained OSF.58,59
collagens.56
Malignant transformation rate of OSF was found to be in the
Rooban (2005) studied muscle involvement in OSF by using range of 7–13% (Tilakaratne 2006). According to long-term
Masson's trichrome stain as this offered a simultaneous contrast follow-up studies a transformation rate of 7.6% over a period of
color to the collagen fibers along with muscle fibers and muscle 17 years was reported (Murti1985). Recently, the
bundles. The collagen stained blue while the muscle stained carcinogenicity of areca nut without tobacco was identified
brilliant red color. This color contrast facilitated a better visual (Jeng 2001) and the second IARC monograph on betel quid has
discrimination between muscle and collagen. The thin collagen classified areca nut as a 'group one carcinogen' based on
fibers were present in between muscle fibers and showed broken epidemiologic and laboratory studies. The strong association of
sarcolemma. Along with this, fibrosis with hyalinization is also areca nut with OSF, its dose-dependent effects and the
seen extending into the muscle bundle zone resulting in atrophy confirmation of OSF as a potentially malignant disease leading
of the muscle. In few cases only the remnants of muscle fibers are to oral cancer provided further evidence for this assertion
seen and the missing muscle bundle area was replaced by fibrous (Johnson 1993). The authors hypothesize that dense fibrosis
tissue. The author considers that the damage to the muscle fibers and less vascularity of the corium, in the presence of an altered
appears more as a consequence of fibrosis rather than by direct cytokine activity creates a unique environment for carcinogens
injury to the muscle by the areca nut products.57 from both tobacco and areca nut to act on the epithelium. It
could be assumed that carcinogens from areca nut accumulate
Malignant potential over a long period of time either on or immediately below the
Oral submucous fibrosis, an insidious chronic disease of oral epithelium allowing the carcinogens to act for a longer duration
mucosa and largely affecting the people of the South East Asian before it diffuses into deeper tissues. Less vascularity may deny
countries, is a precancerous condition. Its precancerous nature is the quick absorption of carcinogens into the systemic
because of higher prevalence of leukoplakia as well as epithelial circulation.6
atypia in this disease leading to oral carcinoma. (Paymaster
1956)16 Murti (1985) assessed the malignant transformation rate in 66
patients at the end of 17years with corresponding median
observation period of 10 years. Oral cancer developed in 5
patients giving malignant transformation rate of 7.6%, all 5

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patients were women who had habit of chewing tobacco and break down hyaluronic acid, lower the viscosity of the
areca nut. Oral cancer developed after 3-16 years after the intercellular cement substance and also decreases collagen
diagnosis of OSMF, the average age of the patients at the time of formation. Intralesional injection of Hyalase (Rallis India) used
development of cancer was 64.6years and the age range was 48- in the dose of 1500 IU, Chymotrypsin (Waltor Bushnell India)
81years. 5000 IU. Fibrinolytic agents (Hyalase) were found to be
acceptable by patients when it was dissolved in 2% lignocaine
This analysis showed OSF possesses high degree of malignant and used in injection. Better results were obtained when a
potential, also with 2 years increase in the observation period, combination of steroids and fibrinolytic agent was used vis-à-
malignant transformation rose from 4.5% to 7.6%60. vis a single agent.37

Dayal (2000) hypothesized intraoral trauma and various factors Placental Extracts (placentrex)
may play a significance role in development of oral cancer such Such extracts, in the form of the local injections, have been tried
as: with varied results. The combination of dexamethasone,
hyaluronidase and placental extract were found to give better
Irritation from jagged teeth results than with a single drug.62
Ill-fitting denture
Sharp overhanging restoration Recombinant Human Interferon Gamma (ã-ifn)
Jacket crowns The experimental evidences show that the increased collagen
Prolong use of tobacco and synthesis in vitro in response to arecoline was inhibited in the
Poor oral hygiene (Hertz 1956). presence of ã-IFN (0.01-10.0U/ml) in a dose related way. The
clinical trials by Hayne using ã-IFN treatment showed
The morphologic manifestation of this chronic mechanical improvements in the patients' mouth opening with a net gain of
trauma is epithelial defect which may form inflammatory 8 ± 4 mm (42%) in the interincisal distance and a range of 4-15
induration either in form of a fibromatous swelling, which will mm62. Rajalalitha, (2005) study hypothesized that, depending
later ulcerate and may lead to development of cancer.61 on molecular events, better therapeutic intervention of the
disease can be made. Some of the possible interventions
Treatment suggested based on the pathway involved are as follows;

In an attempt to cure the disease, several treatment modalities 1. As inflammatory process is the main factor that leads to the
have been developed by various investigators and clinicians. fibrosis, anti-inflammatory/immuno-modulatory drugs
such as colchicines and steroids can be effective. Colchicine
Restriction of habits: is an anti-inflammatory drug that suppresses collagen
Reduction or elimination of habit of areca nut chewing is an synthesis and/or stimulates collagenase. Glucocorticoids
important preventive measure. In early stages of OSMF, it could are an immunosuppressive drug. Presently this is one of the
slow down the progress of the disease. Hence, patients should be important group of drugs used in the treatment of OSF.63
educated regarding the disease and advised to abstain from such 2. TGF-b is an important cytokine involved. The entire pathway
habits.37 that is invoked by it can be suppressed by antibody, which
inhibits its action by interacting with it.
Corticosteroids: 3. LOX is a key enzyme tilting the balance in the collagen
OSMF is always associated with juxta-epithelial inflammatory metabolism towards fibrosis. Inhibiting the activity of LOX
response. The use of corticosteroids suppresses inflammatory either by using a copper chelator like Penicillamine or
response by their anti-inflammatory action. It prevents fibrosis by through another inhibitory mechanism may help in
decreasing fibroblastic proliferation and deposition of collagen. reducing the fibrosis by reducing cross-linking of the
Corticosteroids can be administered as local injection (intra- collagen fibers.
lesional injection), topical applications or in the form of mouth 4. Collagenase activators like colchicine can be helpful in
washes. Widely used preparations are dexamethasone, 4 mg activating the procollagenases thus improving the collagen
biweekly injection, for a period of 10 weeks. Betamethasone degradation process.
(Betnesol) 0.5 mg mouthwash is given to relieve pain and burning
sensation, for topical application triamcinolone 0.1% is given for A combination therapy of the above mentioned drugs thereby
relief of pain and burning sensation.37 intervening at multiple points along the pathway might be
useful for the successful treatment of OSF.63
Hyaluronidase:
Experimental studies revealed that collagen altered in vivo is Microwave Diathermy : Microwave diathermy has been tried
susceptible to fibrinolytic enzymes such as hyaluronidase, trypsin and found to be valuable in the treatment of fibrosis and
and elastase (Satyavathi, Sirsat, Year). Hyaluronidase is known to trismus following dental extraction and other musculoskeletal

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A combination therapy of the above mentioned drugs thereby pithelial surfaces of the normal buccal mucosa and the mucosa
intervening at multiple points along the pathway might be useful in OSF. So extensive research using more numerous samples
for the successful treatment of OSF.63 from different grades of the disease is needed to confirm the
findings in the present study.1
Microwave Diathermy : Microwave diathermy has been tried and
found to be valuable in the treatment of fibrosis and trismus Chung-Hung Tsai (2005) studied expression of Insulin-like
following dental extraction and other musculoskeletal growth factor-1 (IGF-1) in areca quid associated OSF patients
and normal buccal mucosa. He found IGF-1 expression is up
Betel quid chewing habit regulated in OSF than normal mucosa. As this is the first study
done to evaluate the role of IGF-1 expression, the genetic and
environmental determinants of IGF-1expression are still
Chronic incompletely understood. Further research is required to
inflammatory process
detect IGF-1 gene transcripts and know specifically that OSF
1. Anti-inflammatoy/ occurs solely as a result of increased synthesis and deposition of
immuno-modulatory
drugs
IGF-1 by areca nut constitutes.64
TGF-ß

2. Anti-TGF-ß Rooban (2005) conducted light microscopic study of OSF and


found varying degree of alterations involving the muscle fibers
as the disease progresses. He considered that the muscle fibers
Collagen Production Collagen Degradation appear more as consequences of fibrosis rather than by a direct
injury to the muscle by the areca nut products. The factors
PNP PCP TIMP other than fibrosis that restrict mouth opening in OSF cases
Plasminogen need to be explored.57
3. Copper chelators activator
system
H.-F. Tu (2006) aimed to clarify whether the functional
LOX 4. Anti-LOX drugs
nucleotide polymorphism with different promoter activity of
5. Cullagenase Collagenase matrix metalloproteinase 3(MMP3) related to the susceptibility
activators and the disease progression of oral squamous cell carcinoma
and OSF. The study indicated that MMP3 functional promoter
POSSIBLE THERAPEUTIC INTERVENTIONS FOR OSF: polymorphism is associated with the risk of OSF. The genotypic
Some of the possible interventions suggested based on the linkage among the collagen-related genes, MMPs, tissue
pathway involved include: (1) blocking the chronic inflammatory inhibitors of metalloproteinases (TIMPs) and cytokines related
process by anti-inflammatory/immuno-modulatory drugs;(2) to OSF formation requires more information to specify the risk
blocking TGF-b action by anti-TGF-b antibodies or peptide of OSF in areca chewers.67
mimetics of soluble TGF-b receptors; (3) copper chelators like
penicillamine to block LOX activity and prevent cross-linking; (4) Nuclear factor-kappa B (NF-kB) is the collective name for a
other anti-LOX drugs that prevent its action; (5) collagenase group of dimeric ubiquitous transcription factors that comprise
activators like colchicine to promote collagen degradation. the Rel/NF-kB family, which is considered to be important in
Probably a combinational therapy of the above mentioned drugs many inflammatory and immune responses. Aberrant and
thereby intervening at multiple points along the pathway might persistent tissue inflammation is believed to play an important
be useful for the successful treatment of Oral Submucous role on the occurrence of cancer and tissue fibrosis. Areca quid-
fibrosis.63 caused skin hyperplasia and inflammation in CD-1 mice were
associated with the induction of the expression of NF-kB.
Future consideration Recently, areca nut extract was found to activate NF-kB in
Although many researches are on for the prevention and human oral keratinocytes. Studies suggest that the activation of
treatment of OSMF and rehabilitation of the affected patients, NFkB may play an important role in fibrotic diseases, like
further studies are required to understand & prevent the disease idiopathic myelofibrosis and atherosclerosis. The observation
process. of Safrole-induced NF-kB expression suggests that areca quid
chewing may contribute to pathogenesis of OSF via NF-kB
Yoshimura (2005) studied three dimensional morphological expression and associated tissue inflammatory responses.
changes in the connective tissue cores of oral mucosa in OSF
under scanning electron microscope. Though the structural However, more detailed studies should be undertaken to clarify
changes were found at connective tissue cores on the bearing the agents that can regulate NF-kB in vitro and in vivo. Further
surface, no remarkable differences were observed between the e studies will be of importance to address the contribution of
various areca nut ingredients in the areca quid-associated OSF.

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(Wei-Feng Ni 2006)68 OSMF is a precancerous condition with high risk of (7-13%)


malignant development. The orofacial symptoms caused by
Xiaolin Zhang (2006) did study on the Chinese mainland, where this condition disturbs the normal life of the affected persons.6
betel quid (BQ) chewing is common in the Hunan and Hainan
provinces. Oral diseases associated with BQ chewing are oral Etiopathogenesis of this disease is not conclusive till today,
submucous fibrosis (OSF), oral leukoplakia (OL) and oral cancer. however the role of many factors such as chillies, genetics,
Reported prevalence of OSF among BQ chewers ranges from 0.9% tobacco, areca nut, immunological factors, nutritional
to 4.7%. In BQ chewers the prevalence of oral cancer ranged from deficiencies, autoimmune disease have been implicated. The
0.02% to 0.05%. In cases of OSF, reported oral cancer prevalence recent concepts reveal the molecular level of pathogenesis,
is 2.6% and 1.2%. Presently, data on prevalence of BQ chewing in which will also aid in treatment modalities that can be used as a
southern provinces of Mainland China is limited. BQ chewing ladder for improved treatment of the disease and thus improve
habits, however, seem to differ between geographic areas. the lifestyle of the affected population.2,6
Future case–control studies are necessary to evaluate the risk for
oral cancer and other associated oral mucosal diseases resulting The disease starts with initial symptom of burning sensation,
from variations in BQ chewing habits.69 experienced on consuming spicy foods and inability to swallow
the normal saliva due to involvement of tongue, with altered
Chang (2005) reported that betel quid (BQ) chewing has strong taste sensation. In the advanced stages of the disease, the
association with the risk of oral leukoplakia (OL), oral submucous mouth opening decreases with accompanying dysphagia.15
fibrosis (OSF), and oral cancer (OC). BQ components exhibit
genotoxicity and may alter the structure of DNA, proteins and On examination of the oral cavity the mucosa appears normal in
lipids, resulting in production of antigenicity, and also shown to color initially; it looses its resiliency, suppleness and becomes
induce keratinocyte inflammation by stimulating the production stiff as disease progresses. Depending on the severity, OSMF is
of prostaglandins, TNF-a, IL-6, IL-8, and granulocyte-macrophage graded by many authors. The involvement of various regions of
colony-stimulating factor (GM-CSF) in keratinocytes. These oral cavity and its characteristic clinical feature depends upon
events may provoke tissue inflammation, early cell-mediated the type of chewing habit.37,38
immunity (CMI), and immune surveillance in BQ chewers.
However, BQ components also directly affect the functional Both light and electron microscope findings of the disease are
activities of immunocompetent cells, and moreover tumor cells reported. The disease shows both epithelial and connective
may hypo-respond to the CMI via diverse mechanisms such as changes, in which epithelial changes are secondary to changes
induction of apoptosis of lymphocytes, induction of production in the connective tissue. The epithelium shows atrophy, loss of
of suppressor T cells, down regulation of MHC molecules in tumor retepegs, intercellular edema, and vacuolization of prickle cell
cells, etc. Clinically, an alteration in lymphocyte subsets, a layer. The connective tissue change depends on the stage of the
decrease in total number of lymphocytes, and a reduction in disease, where in early stages it shows fine fibrillar dispersed
functional activities of CMI have been observed in isolated collagen with marked edema, undergoes hyalinization and is
peripheral blood mononuclear cells (PBMC) and tumor infiltrated seen juxtaepithelially. The inflammatory exudate consists of
lymphocytes (TIL) in patients with OSF, OL or OC. lymphocytes and plasma cells. The collagen is completely
hyalinized in advanced changes, which obliterates the blood
Future studies are needed to evaluate whether virus infection, vessels.46
tobacco smoking, alcohol drinking, BQ chewing, and other
environmental exposure may affect the local and systemic Ultrastructurally epithelial cells show reduced number of cell
immune status in patients with oral premalignant lesions (OL, organelles and tonofilaments with pyknotic nuclei in which the
OSF, erythroplakia) or OC. In addition, more in-depth chromatin is marginated. Collagen fibers show abnormal
investigations are needed to clarify the diversities of immune- fragmentation without true bundle formation.49
related genes in different races of people in the world and to
elucidate whether people of different races may have different Special investigation by stains, such as Van Gieson, Masson's
susceptibilities to OC and OSF.70 Trichrome, immunogold silver staining, MHC Class II antigen
expression, procollagen type III & collagen type IV expression
are studied. These immunohistochemical stains provide the
Summary evidence for disease process. It indicates that the fibrosis starts
OSMF is a precancerous condition with high risk of (7-13%) deeper in subepithelial connective tissue stroma, not close to
malignant development. The orofacial symptoms caused by this subepithelial basement membrane. Recently it is also found out
condition disturbs the normal life of the affected persons.6 that muscles also show atrophy in OSMF.52-55

Numerous treatment modalities have been implicated to cure


the disease such as use of corticosteroids, hyaluronidase,

1 Journal of Health Sciences and Research, Volume 2, Number 1, April - 2011


Review Article

placentrix, IFN- and microwave diathermy etc. Surgical treatment 14. Gupta PC, Mehta FS, Daftary DK et al. Incidence rates of oral
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defect with grafts.37,63 10 year follow up study of Indian villagers. Community Dent
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The researches have studied expression of Insulin like growth 15. Prabhu, Wilson, Daftary & Johnson. Oral diseases in the
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each study.67-70 17. Murti PR, Bhonsle RB, Gupta PC et al. Etiology of oral
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1 Journal of Health Sciences and Research, Volume 2, Number 1, April - 2011