\

Available online at www.sciencedirecl.com BRITISH

Journal of
SciVerse ScienceDirect Oral and
Maxillofacial
ELSEVIER Surgery
Bri tish Journal Pf Oral and Maxillofodal Surg~ry 51 ('.!0 13) 587- 593 •
www.bjoms.com

Oral submucous fibrosis: an overview of the aetiology,

pathogenesis, classification, and principles of management
Gururaj Arakeri a, *, Peter A. Brennan b
• Department of Oral and Max1·u0,r. • IS . . .
bQ ,ac,a urgery, Navodaya Dental College and Hospital, Ra,chur. Karnataka, India
ueen Alexandra Hospital, Cosham, Portsmouth P06 3LY, United Kingdom
Accepted 28 August 2012
Available online 26 October 2012

Abstract

Oral submucous fibrosis (OSMF) is a complex, debilitating, and precancerous condition. Fonnerly confined to the Indian subcontinent, it is
now often seen in the Asian populations of the United Kingdom, USA, and other developed countries, and is therefore a serious problem
for global health. The well-known causative agent of the disease, areca-nut is now recognised as a group one carcinogen. We review and
discuss all components of OSMF, including the tenninology, presentation, aetiology, and pathogenesis, and provide a brief overview of its
management.
© 2012 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Keywords: Oral submucous fibrosis; Areca-nut; Gutkha; Aetiology; Pathogenesis; Review

Introduction significantly increased risk of cancer" fits well with the

characteristics of OSMF. 4·5 The condition is thought to be
Oral submucous fibrosis (OSMF) is a chronic, debilitating multifactorial in origin with a high incidence in people who
disease characterised by juxtaepithelial fibrosis of the oral chew areca-nut, 6 and a significant malignant transfonnation
cavity. It is regarded as a precancerous and potentially malig- rate (7-30%)7 poses global problems for public health. The
nant condition. l ,::? The most widely accepted definition of the physical effects, which include a burning sensation in the
disease by Pindborg and Sirsat3 is one of an insidious, chronic mucosa and progressive trismus, can also have psychological
disease that affects any part of the oral cavity and sometimes and social implications for patients.
the pharynx. Although occasionally preceded by, or associ-
ated with, fonnation of vesicles, it is always associated with a
juxtaepithelial inflammatory reaction followed by fibroelas-
tic change of the lamina propria and epithelial atrophy that Terminology
leads to stiffness of the oral mucosa and causes trismus and
an inability to eat. 3 In 1952, Schwartz described a condition in 5 Indian women
The definition by the World Health Organization that he called "atrophia idiopathies (tropica) mucosae oris"
(WHO) of an precancerous oral condition: "a generalized (Schwartz J. Atrophia idiopathica (tropica) mucosae oris.
pathological state of the oral mucosa associated with a Presented at the Eleventh International Dental Congress,
London, I952); Joshi coined the tenn "submucous fibrosis
of the palate and pillars". 8 Other names suggested include
• Corresponding author at: Gangashri Nilaya, Basaveshwara Nagar, Sha-
"diffuse oral submucous fibrosis", "idiopathic sclerodenna
hapur 585223, Yadgir, Kamataka, India. Tel.: +91 9341428302; of the mouth", "idiopathic palatal fibrosis", and "sclerosing
fax: +91 9663420867. stomatitis".3-4 Pindborg and Sirsat used the term "submucous
E-mail address: gururaj.ar:[email protected] (G. Arakeri). fibrosis" although they suggested that a more appropriate

0266-4356/$ - see front matter e 2012 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved,
http://dx.,fai.org/l 0. IO 16/j.bjoms.20 I2.08.014
r
588 G. Arakeri. P.A. Brennan I British Journal of Oral and Maxi//ofacial Surgery 51 (20/ 3) 587-593

southern states, and Taiwanese.10•18 Other series of OSMF

in Europe, the Far East, and the Pacific Rim have been
reported. 7-10-I8 An estimate from 1996 indicated that glob-
ally, about 2.5 million people have OSMF, 7 but studies have
found that over 5 million people are affected in India alone
(0.5% of the Indian population). l .7. l 9 It is also estimated that
up to 20% of the world's population use betel nut in some
form, so the incidence of OSMF is likely to be much higher
than current estimates suggest, and it is regarded as a pub-
lic health issue in the Indian subcontinent, the UK,.1·20 and
South Africa.l.7,21 It is predominantly seen in the second or
third decade, and recent data suggest a male predominance;
however, both sexes are equally at risk. 10•18 Oral cancer that
arises in those who chew betel quid is one of the most common
malignancies in south and southeast Asian countries, 1•22 and
with immigration from the Indian subcontinent to the UK,
USA, and South Africa, oral and maxillofacial surgeons in
Fig. l. ~inical appearance oforal mucosa in oral submucous fibrosis (A-C) these countries are likely to encounter the disease more often
and malignant changes in the condition (marked with arrows in D). in future.7

name would be "juxtaepithelial fibrosis".-3 Its premalignant

nature was first described by Paymaster in 1956.9
Aetiology

Clinical presentation At first, OSMF was thought to be idiopathic, but it was later
concluded to be multifactorial in origin, and possible aetio-
Clinical presentation depends on the stage of the disease.10 logical factors include capsaicin in chillies, iron, zinc, and
~itially, most patients present with a burning sensation or deficiencies in essential vitamins. 6· 18-23 •24 Various autoan-
mtolerance to spicy food, and they may have vesicles, partic- tibodies and specific human leucocyte antigens (HLA) in
ularly on the palate. Ulceration and dryness of the mouth is some patients have indicated an autoimmune role as well
later followed by fibrosis of the oral mucosa, which leads to as a genetic predisposition for the disease.25 However, var-
rigidity of the lips, tongue, and palate, and trismus. 10 ious epidemiological studies, large cross-sectional surveys,
Petechiae, in the absence of blood dyscrasias or systemic case-control studies, and cohort and intervention studies have
disorders, are found in about 22% of patients with OSMF, provided overwhelming evidence that areca-nut is the main
and occur most often on the tongue followed by the labial aetiological factor in OSMF. 2 1.25 - 34 The nut is the endosperm
and buccal mucosa. 4- 11 of the fruit of the Areca catechu palm tree.7 A range of
A useful clinical sign is pain on palpation in the sites where case-control studies have given convincing evidence that
submucosal fibrotic bands are developing, 11 and trismus is there is a definite dose-dependent relation between areca-
caused mostly by fibrosis in the dense tissue around the ptery- nut and causation of the disease, and it is well known that the
gomandibular raphae. 11 Fibrosis of the eustachian tube may onset of the disease is directly proportional to the concen-
lead to deafness. 7•12 When the fibrosis involves the nasopha- tration, incidence, and duration of chewing the nut (without
25
rynx or oesophagus, patients may experience referred pain to tobacco ). ·29·32..l4 Generally, younger patients develop clini-
the ear, a nasal voice, and dysphagia to solids; usually these cal features of OSMF within 3.5 years from onset of the habit
are.features of more advanced disease. 7· 11 while in older patients it takes 6.5 years. 25,27
The most obvious clinical signs include blanched, opaque Currently, in India, Pakistan, and Bangladesh, betel quid
oral mucosa with palpable fibrous bands (Fig. I ). 10.1 3,14 Fur- and gutkha are the most commonly used commercially
thermore, the overlying epithelium may become dysplastic freeze-dried areca-nut products. Gutkha (also spelled gutka
and malignant. Restricted mouth opening interferes with or guthka, thought to be derived from Hindi meaning "a shred
examination of the oral mucosa, and makes early diagnosis or small piece") is a light brown, grainy powder available in
of cancer a daunting task. 10•15 - 17 compact storable sachets (Fig. 2). It consists mainly of areca-
nut, tobacco, and flavours, and is typically taken to relieve
stress. When chewed it dissolves quickly in saliva and pro-
Epidemiology vides central stimulation, which is said to be more intense
than tobacco.
Geographically, OSMF has a spe~ific distribu~ion and affects Gutkha has replaced most of the commercial areca-nut
predominantly Asians (and particularly Indians) from the preparations, and contains the nut in high concentrations
 589
G. Arokeri, P.A. Brennan I British Journal of Oral and Maxillofacial Surgery 5 l /2013) 587-593

on increased synthesis, or reduced degradation, of collagen, 25

as possible mechanisms in the development of the _disease _ ;
there are changes in the normal collagen metabolism at dif-
ferent stages.
Areca-nut contains alkaloids, flavonoids, and copper,
which all interfere with homeostasis of the extracellular
matrix. Four alkaloids - arecoline (most potent), arecaidine,
guvacine, and guvacoline-are known to stimulate fibrobl~ts
to produce collagen.25 Flavonoids (tannins and catechins)
inhibit collagenase, stabilise the collagen fibril~ and render
10
them resistant to degradation by collagenase. ,!5
The localised mucosa} inflammation caused by areca-
nut or gutkha results in the recruitment of activated T-cells
and macrophages that lead to an increase in cytokines and
Fig. 2. Picture showing betel leaf (A), a typical betel quid (B), contents of tumour growth factor beta (TGF-!3).1 The latter cons1'd-
a tobacco betel quid with areca-nut (C), compact sachets of gutkha (D) and erably increases the production of collagen by activ~ting
contents (E). Note the increased load of areca-nut compared with betel quid. procollagen genes, and upregulating procollagen protemase
enzymes and lysyl oxidase activity.7 ·36 Simultaneously, TGF-
along with tobacco. Betel quid commonly contains areca-nut 13 inhibits collagen degradation by activating the tissue
(incorrectly known as betel nut), slaked lime, and A. catechu inhibitor of matrix metalloproteinase (TIMP) genes and plas-
with or without tobacco, and is typically wrapped in betel minogen activator inhibitor (PAI).7 The high concentration
leaf (from the Piper betle, a pepper shrub). 7 Although it is of copper in areca-nut has been found to stimulate lysyl oxi-
still often chewed (usually after meals and thought also to dase activity, an enzyme essential to the final cross-linking of
be an appetiser) in India, its consumption as an addictive collagen fibres.1•7 Increased copper has been seen in mucosa
habit has reduced. However, consumption of the addictive affected by OSMF, which supports its role in fibrogenesis by
gutkha is increasing rapidly and its increased popularity may enhancing lysyl oxidase activity. 1o,'.17-40
be because it is easily accessible, and because of effective Continually chewing areca-nut leads to increased activ-
changes in price and marketing strategies. ity of the masticatory muscles, depletion of glycogen, and
Unlike pan masala, which has to be freshly prepared before muscle fatigue. The reduced blood supply following fibro-
use, gutkha is available in compact sachets, which are easy to sis further promotes muscle fatigue and causes extensive
41
handle, and allow it to be consumed at any point during the degeneration and fibrosis in the muscles.
day. The habit often starts among young people, usually as a As previously mentioned, another two possible over-
fashion or status symbol, because of peer pressure, or to imi- lapping mechanisms are autoimmune factors and genetic
predisposition. 10 This has been substantiated by the pres-
tate parents. It is often used by adults (such as taxi drivers or
merchants) to cope with irregular meals, to relieve stress, or to ence of circulating immune complexes, immunoglobulins,
15 and autoantibodies in some patients with OSMF, as well
stay awake during shift work, and even to relieve toothache:
It is more highly addictive than ordinary chewing tobacco and as altered cellular and humoral responses. 10.25,42-47 Genetic
is exported to well over 22 countries.3
5 susceptibility is supported by raised HLA-A 10, -B7, and DR3
Gutkha is usually placed into the buccal or labial vestibule in OSMF patients compared with normal controls. 11 The
(and sometimes beneath the tongue), and is chewed for up familial occurrence of the disease has been reported from
to an hour until the nut softens and dissolves completely in India and South Africa. 10-25 .-1s-5 t
saliva. The excess is either spat out or swallowed. It is typi- It seems likely that OSMF is a multifactorial disease with
cally done several times and more in those who are addicted. initiators, promoters, and other modifying cofactors. But the
Many patients place it in the buccal vestibule at night while tenet- loss of equilibrium of extracellular matrix and continu-
ous deposition of extracellular matrix - in OSMF is currently
they sleep.
well accepted. 10

Pathogenesis
Classification schemes for OSMF
7
OSMF is essentially a disease of collagen metabolism, but
despite research spanning more than 3 decades, its pathogen- Several classification and staging systems based on different
esis is still not fully understood. There is compelling evidence aspects of the disease have been suggested.5'.! The earliest
that the areca-nut has a primary role in the development of classification by Pindborg and Sirsat3 in 1966 was based
10 15
OSMF (Fig. 3), but it has yet to be elucidated. • However, on histopathological features and was updated in 2005 by
it seems that changes that occur in the extracellular matrix Utsunomiya et al. 36 The main disadvantage of them is the
are likely to have a key role.25 These studies have focused absence of any description of the epithelial component of the
 590
G. Arakeri. P.A. Brennan I British Jou ma/ of Oral and Maxil/ofacia/ Surgery 5I (2013) 587-593

Areca-nut

r I
A/Ira/olds
I
Flavonolds
I l
Copper

l
Constant chewing

Arecoline
l
Tannin and
!
Increased

I
catechin concentration
of soluble copper

l In saliva

l
Hydrolysis
(enhanced by addition of Inhibition of
slaked lime, Ca(OH)z) collagenase

!
Arecaidine
Upregulation of
lysyl oxldase activity

Guvacine,

l _J
Pronounced
guvacoline
Muscular contracture
proliferation of
fibroblasts

l
'"'=':"'9 00
-o:. ~a/~down
of Insoluble collagen

r __ 1
Oral sut>mucous fibrosis
Overactivity of
masticatory
Juxtaepithelial hyalinisation and perioral musculature

!
Vaso-obliteration - Reduced blOOd supply - - - - Depletion of glycogen
l
Muscular fibrosis and - - - Muscle fatigue and
!
scarring degeneration

l
Pronounced limitation of mouth opening

Fig. 3. Role of areca-nut in the pathogenesis of oral submucous fibrosis.

52
disease. Wahi et al. 53 presented the first clinical classifi-
cation (of 3 groups) based on symptoms, and several others genotoxic and mutagenic effects are attributed to polyphe-
have now been proposed. 11•12•54-<iOHowever, one well known nols, alkaloids, and areca-nut-specific nitrosarnines
and respected staging system (Khanna and Andrade41) has such as N-nitrosoguvacoline, N-nitrosoguvacine,
successfully combined histopathological and clinical features 3-(N-nitrosomethylamino)propionaldehyde, and 3-(N-
nitrosomethylamino)propionitrile. 10-57 Various studies
of the disease, and was developed mainly to aid in surgical
management. have been conducted in an attempt to identify molecular
markers that could be used to predict malignant change in
OSMF. Recently, a loss of heterozygosity in 23 "hotspot"
loci which alter genes that control the cell cycle has been
recognised as an important molecular marker for malignancy
Malignant transformation and molecular markers in OSMF, IU,63

OSMF has a malignant transformation rate of 7-30%

7 12
(Fig. 10). • Pathogenesis is thought to be multifactorial.
Overview of management principles for OSMF
The carcinogenic effects of tobacco acting in synergy with
areca-nut is well known, but the second report on betel quid Patients with OSMF characteristically complain of two prob-
by the International Agency for Research on Cancer (IARC) lems: an inability to open the mouth, which impedes function,
• •
identified areca-nut as a " group one carcinogen
· .. , 10·61.62 Its
and a burning sensation and intolerance to spicy foods
I Table I
G. Arakeri. P.A. Brennan/ British Jou rna/ of Oral a11d Ma:cillofacial Surgery 5/ (20/3) 587-593

Management of oral submucous fibrosis.

Surgical therapy Conservntive therapy
591

Rationale: incision (incorrectly tenned as ex . . ) . Physical therapy

fibrous bands followed b . cision or surgical release of Physical exercise regimen
incised tissue or region) y f~rceful _o pemng o~ the mouth (widening of the Splints or other mouth opening devices
synthetic biological ma;e:;'al covenng of surgical defects using various naps or Microwave diathenny
Medical therapy
Extraoral flaps Modulators of inftammntion:
Split thickness skin graft Steroids
Superficial temporal fascia pedicled Hap Interferon gamma
Temporalis pedicled flap Placental extracts
Nasolabial flap Immunised milk
Amnion graft Modulators of vascularity or relief of ischaemia:
Platysma myocutaneous muscle Hap Pentoxiphylline
Intraoral flaps Buftomedil hydrochloride
Tongue flap Nylidrin
Palatal island flap Nutritional support and to combat reactive oxygen species:
Buccalfatpad Beta-carotene
Microvascular free flaps Lycopene
Radial foreann free llap Vitamins
Anterolateral thigh flap Micronutrients
Alloplasts Fibrinolysis:
Collagen membrane Collagenase
Artificial dermis Hyaluronidase
Chymotrypsin
Ayurvedic treatment:
Tunneric (Curcuma longa L .)
Tea pigments
Oxitard

effect - more on the symptoms of OSMF than on reversing

(intolerance to normal diet in severe cases). Management
aims to reverse or alleviate these signs and symptoms, stop fibrosis.
the disease progressing, and minimise the risk of malignant
transformation. 64 Conclusion
The current protocol for the management of OSMF can
be divided into 3 broad groups: surgical, physical, and med- As management of OSMF aims to slow the progression of
ical treatments (Table I). Surgical treatment, used mainly to the disease, better legislation to govern the availability and
manage trismus, involves incising and releasing the fibrotic sale of areca-nut is recommended, although implementation
10
areas, and leads to further scarring and fibrosis. The intro- 65 of this may not be practical at present.
duction ofremote tissue (pedicled, such as a buccal fat pad,
nasolabial or platysmal flaps, 66 or free tissue transfer) in an
attempt to release fibrosis 67 •68 is one approach but results are Funding
variable. BAOMS Endowment grant for OSMF research awarded to
Physical treatment attempts to influence the remodelling
of tissue by using movement - for example, exercises G. Arakeri.
and physiotherapy, 58 ,69 various splints or other devices to
improve mouth opening, 70-n or localised heat (such as with
56 74 References
microwave diathermy ·B. ).
Medical treatment includes dietary supplements (vita-
I. Rajalalith,\ P, Vali S. M(.)\ecular pathogenesis of ora\ submu-
mins, antioxidants), the use of anti-inflammatory drugs cous !ihn,si,-c1 collagen mct.1bolic disorder. J Oral Plllhol Med
(principally corticosteroids), proteolytic agents (such as
2005:34:321-8.
hyaluronidase), anticytokines, and other agents that are not 2. Pindborg JJ. M11rti PR. Bhon~le RB, Gupta PC, Daftary DK, Mehta FS.
available in the UK. They can be given orally, topically, or Oral s11hm11cous fibwsis as a precancerous condition. Scand J Dtnr Res
58 64 75 90 t 984;92:n4--9.
by submucosal injection. · · - 3. Pindborg: JJ. Sirsat SJ\t Oral submucous fibrosis. Oral S1u-g Oral Med
Operation is generally reserved for established cases of
Oral f'ntlrol !966:22:764-79.
OSMF while physical treatment is usually combined with all 4. Rajendran R. Oral submucous librosis: etiology, pathogenesis, and future
64
other interventions. However, Kerr et al. recently hypothe- 1\!Sl'arch. 8111/ World Jlealllr Organ 1994:72:985-96.
sised that cessation of the habit alone may have a considerable