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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
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.
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
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
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
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
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
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
placentrix, IFN- and microwave diathermy etc. Surgical treatment 14. Gupta PC, Mehta FS, Daftary DK et al. Incidence rates of oral
is also considered by excision of fibrotic tissues and covering the cancer and natural history of oral precancerous lesions in a
defect with grafts.37,63 10 year follow up study of Indian villagers. Community Dent
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