You are on page 1of 9

J Oral Pathol Med 1995: 24: 145-52

Printed in Denmark . All rights reserved

Copyright Munksgaard 1995


JOURNAL OF

Oral Pathology&Meciidiie
ISSN 0904-2512

Review article

Etiology of oral submucous


fibrosis with special reference
to the role of areca nut chewing

^P. R. Murti, ^R. B. Bhonsle,


ip. C. Gupta, ^D. K. Daftary,
^J. J. Pindborg and ^Fali S. Mehta
^ Basic Dental Research Unit and WHO
Collaborating Centre for Oral Cancer
Prevention, Tata Institute of Fundamental
Research, Bombay, India, ^School of Dentistry,
Faculty of Health Sciences, University of
Copenhagen, Denmark

Murti PR, Bhonsle RB, Gupta PC, Daftary DK, Pindborg JJ, Mehta FS: Etiology of oral submucous fibrosis with special reference to the role of areca nut
chewing. J Oral Pathol Med 1995; 24: 145-52. Munksgaard, 1995.
Oral submucous fibrosis (OSF) is a high risk precancerous condition, predominantly affecting Indians. Consumption of chilli was hypothesized as an etiologic
factor on the basis of ecological observations and a solitary animal experimental
study. Subsequent epidemiologic studies that included case-series reports, large
cross-sectional surveys, case-control studies, cohort and intervention studies have
identified areca nut as the major etiologic agent. Tissue-culture studies involving
human fibroblasts, areca nut extracts and areca nut alkaloids supported this etiologic hypothesis by showing fibroblastic proliferation and increased collagen
formation. Currently, the role of genetic susceptibility and that of autoimmunity
are receiving attention. The influence of nutritional factors, if any, remains unclear.

Oral submucous fibrosis (OSF) is a


chronic condition characterized by
mucosal rigidity of varying intensity
due to fibro-elastic transformation of
the juxta-epithelial layer. This leads to
restricted oral opening; when the
tongue is involved, its protrusion may
be impaired. Most affected individuals
report a burning sensation of the oral
mucosa aggravated by spicy food. The
presence of palpable fibrous bands is a
requisite diagnostic criterion for this
condition, as otherwise other mucosal
conditions such as anemic states are
likely to be diagnosed as OSF, especially
in field studies. Unfortunately, all investigators have not strictly adhered to this
criterion in the past.
OSF has been predominantly reported among Indians living in India as
well as outside, to a lesser extent among
other Asiatics and, sporadically, among
Europeans. With a reported prevalence
ranging up to 0.4% in Indian rural
populations (1), several million individuals are estimated to suffer from this

malady. OSF is a precancerous condition (2) with mahgnant transformation


rates as high as 7.6% (3-5) and a relative risk of 397.3 for oral cancer development compared to individuals with
tobacco habits but without any precancerous lesion or condition (5).
Several factors such as chilli consumption, nutritional deficiency states,
areca nut chewing, genetic susceptibility,
autoimmunity and collagen disorders
have been suggested to be involved in the
pathogenesis of this condition. Some of
these suggestions were based on ecological observations, others were more or
less speculative. It is the purpose of this
paper to summarize and critically analyze the considerable body of evidence
which implicates areca nut in the etiology of this condition. Brief reference will
be made to other suggested etiologic factors for which less satisfactory evidence
exists. Finally, a short description on the
pathogenic mechanism in OSF is included, as this aspect has been inadequately
investigated so far.

Key words: areca nut: epidemiology, oral:


etiology: mouth, diseases: precancer:
submucous fibrosis, oral
R R. Murti, Basic Dental Research Unit,
Tata Institute of Fundamental Research,
Homi Bhabha Road, Colaba,
Bombay 400 005, India.
Accepted for publication October 15, 1994.

Historical aspects
OSF was first described by SCHWARTZ
(6) in 1952 among five East African
women of Indian origin. This was followed by the first description of this
condition in India in 1953 in quick succession by LAL (7) and JOSHI (8). The
first report among non-Indians was
from Taiwan by Su (9) in 1954. Most of
the large studies have been reported
from India (1, 7, 8, 10-21), Pakistan
(22), Indians in South Africa (23-25),
and from Taiwan (26); people from India, Kenya, Uganda, Malawi and Pakistan living in the UK are also affected
(27) (Table 1). The disease has been reported from Sri Lanka (28), Myanmar
(formerly Burma) (29) and Bangladesh
(30) as well as from Nepal, Malaysia,
Singapore, Thailand, China, South
Vietnam and Fiji (31), Papua New
Guinea (32), Saudi Arabia (33), Asians
in Kuwait (34), the USA (35), Canada
(36) and sporadically among Europeans
(37-39). The characteristic occurrence

146

MURTI et al.

periments. Nevertheless, the results of


the earlier experimental study (40) have
been cited widely in the literature in favor of the etiologic role of chillies.
From the observation of blood eosinophiha (10, 15), tissue eosinophils in the
Etiology
biopsy specimens (31, 41, 42), subepithChilli
elial vesicles (41) among patients with
The suspicion that chilh is an etiologic OSF, and considering the experimental
agent arose on the basis of ecological findings reported earlier (40), PINDobservations and was strengthened by BORG & SINGH (41) suggested an allergic
the clinical and histologic characteris- nature of this disease possibly due to
tics of this condition. OSF is found chilli intake.
Some epidemiologic studies have admostly among Indians and other population groups who use chillies {Capsi- dressed the etiologic role of chillies. In
cum annum and Capsicum frutescence) a study of 104 cases and controls in Into spice their food. A frequent observa- dia in 1966, the role of chilh consumption is that OSF patients are unable to tion was assessed (15) but no significant
tolerate spicy food containing chillies differences as to the amount of chilli
which form a part of their normal diet consumption per month or the age of
before they develop the disease. Sup- starting chilli consuriiption was found.
port from histologic observations was In a Taiwanese study of 35 cases and
100 controls in 1979, SHIAU & KWAN
provided in an evaluation of 85 palatal
biopsies from OSF patients by SIRSAT & (26) found no association between chilli
consumption and OSF. In South Africa,
KHANOLKAR (40). They observed epithelial hyperplasia, presence of a chron- where the prevalence of OSF is high
ic inflammatory cell exudate, and dense among people of Indian origin, SEEfibrogenesis with elastotic degeneration DAT & VAN WYK (25) did not observe
of collagen; these changes were thought any significant difference in the type
to indicate a simultaneous defense and and the amount of chillies consumed
repair mechanism, similar to the chron- between 71 OSF patients and 103 betel
ic productive response. This response is chewers without this condition. Indirect
present where the agent responsible for observations from a 10-yr prospective
exciting an inflammatory reaction is study in Ernakulam district, Kerala, Inmild and continues to operate over a dia, also did not substantiate the etioprolonged period of time. The hypo- logic role of chillies. For example, GUPthesis of chilli as an etiological agent TA et al. (43) observed 30,962 personyears of nonusers of areca nut (betel
fitted with these observations.
An animal experimental study using quid) and other forms of tobacco,
capsaicin, an active principle of chillies, 20,222 person-years of smokers, 23,111
as a test substance has been conducted person-years of chewers and 8456 peron Wistar rats (40). The investigators son-years of smokers and chewers, of
observed elastotic degeneration of pala- both genders, to obtain incidence rates
tal collagen, and ultrastructurally par- of this condition. Although there were
tial or complete degeneration of the col- substantial person-years of observalagen into elastin-hke filaments, sheets, tions in different groups, and their food
or dense amorphous material. It was in- habits in general were similar, all cases
ferred that capsaicin was capable of of OSF were observed only in those
evoking a limited connective tissue re- who chewed areca nut (in betel quid).
sponse in an unimpaired animal system
There are some ecological arguments
and the reaction was enhanced in against the chilli hypothesis. For examprotein- or vitamin-deficient animal ple, from Mexico or other South Amersystems. The authors, however, cau- ican countries where chilli consumption
tioned that although the optical and is widespread, we are not aware of any
submicroscopic changes of collagen in report on this condition. The overall astheir studies were comparable to human sessment is that there is no evidence
OSF of the palate, it did not necessarily substantiating the etiologic role of chillimplicate chilh as the sole causative ies in OSF.
agent because the alterations seen were
Interestingly, however, in recent years
nonspecific and indicated only a reac- short term experimental tests have
tion to irritant. In contrast to the re- shown chilli extract to be mutagenic
sponse observed by these investigators (44) and it has also been found to enHAMNER et al. (35) failed to reproduce
hance the tumorigenicity of tobacco in
the results in hamster cheek pouch ex- experimental animals (45). Furtherof OSF among Indians and other Asiatics has prompted many investigators to
search for etiologic factors that may be
a part of their diet or environment.

more, epidemiologic studies have shown


that chilh consumption increases the
risk of cancers in the upper aerodigestive tract in a dose-dependent manner
(46).
Nutritional deficiencies

Several investigators have reported anemia, vitamin, iron and protein deficiencies among OSF patients (6, 10, 1315, 23). Because of the presence of iron
deficiency anemia in 10 of 13 OSF patients in Malaysia, RAMANATHAN (47)
hypothesized that this condition was an
Asian version of sideropenic dysphagia
wherein the chronic deficiency leads to
mucosal susceptibility to irritants such
as chilli and areca nut use. Some of
these observations were supported by
case-control studies. For example, a
higher frequency of clinical manifestations of deficiency of vitamins A,B and
C, and lower serum vitamin levels were
found in cases as compared to controls
by WAHI et al. (15); no significant difference in the frequency of anemia between the cases and controls was observed. In a South African study, there
was no difference in the prevalence of
iron deficiency anemia between that observed in the cases and the general
population (24). Serum folate and B12
levels were also within normal limits in
this study.
The above observations did not estabhsh an etiologic or contributory role
for nutritional deficiencies in OSF. It is
probable that the deficiency of these
factors observed among OSF patients
may be secondary; most OSF patients
cannot tolerate spicy food, which is a
normal family and community diet, and
the opening of the mouth in OSF patients becomes progressively smaller.
This functional impairment may affect
normal food intake and lead to nutritional deficiencies.
Areca nut use

Currently, areca nut use is considered to


be the most important etiologic factor
for OSF
Areca-nut chewing habits

Areca nut (often erroneously referred to


as betel nut) is the endosperm of the
fruit of the Areca catechu tree. The fruit
is orange-yellow in color when ripe. The
fibrous pericarp is removed from the
seed or endosperm, which is then used
fresh, after sun drying or in a cured

Etiology of submucous fibrosis 147


form. Areca nut contains tannins (11.426.0%), of which gallotannic acid
(18.03%) and D-Catechol (0.4%) are
important (48, 49). It contains several
alkaloids (0.15-0.67%) of which arecoline is the most abundant; arecaidine,
guvacine, isoguvacine, arecolidine and
guvacoline are also present in small
quantities. Other substances comprise
fats, carbohydrates, proteins, and mineral matter. In India areca nut is chewed
by itself, in the form of various areca
nut preparations such as scented supari,
mawa, mainpuri tobacco, pan masala,
and in betel quid, either with or without
tobacco (50). Areca nut chewing is also
practiced in various forms in several
countries in South East Asia, Oceania,
and the Pacific Islands and by Indian
emigrants living abroad (24, 49, 51).
Epidemiologic studies

The studies that have led to the identification of areca nut chewing as an etiologic factor for OSF include ecological
observations, case reports, case-series
studies, case-control studies, cross-sectional studies, prospective studies, and
intervention studies. The concept has
been strengthened by the demonstration of a dose-response relationship and
by the regional variation in clinical features of the disease that are Hnked with
the type of areca nut use.
Ecological observations - The occurrence of OSF in an area or population
in which areca nut chewing is popular,
compared to its rarity in populations or
areas where areca nut chewing is unknown or less common, constitute the
ecological observation. In South Africa
OSF is common among women of Indian origin and rare among blacks (24).
This corresponds with the fact that areca nut chewing is often practiced by the
Indian women but rarely by South African blacks. In Bhavnagar town, Gujarat, India, there was a sudden upsurge of
this condition (52) with 275 cases being
recorded in a recent 5-yr period as compared to very few cases observed earher.
This trend corresponded with the
increase in an areca nut {mawa) chewing
habit in that area. Ecological observations can point towards a possible
hypothesis, but are weak for inferring
any causal relationship.
Case reports - These comprise reports on OSF cases indicating the presence of an areca nut chewing habit
among the patients involved. For example, Su (9) reported that all 3 cases he
observed chewed areca nut and he hy-

pothesized that OSF may have been


caused by the tannic acid, slaked lime
powder and the continued action of arecoline affecting the "vascular nerves" of
the oral mucosa and causing "neurotropic disorder". Case reports also include anecdotal observations such as
the occurrence of this condition in a 4yr old Indian immigrant girl in Canada
who had been chewing areca nut since
the age of 2 (36)!
Case-series studies - These comprise
a large number of reports by various investigators over a 27-yr period from
which the frequency of areca nut chewing could be extracted. Table 1 shows
that areca nut chewing was practiced by
31-100% of the cases. Despite lacking
controls, these studies indicated that the
frequency of areca nut chewing was
probably far higher than was expected
or known in the unaffected group or in
the general population. These data have
limitations as the studies were conducted at various points over a long time
span and with differing concepts of the
diagnostic criteria and the etiology of
the disease.
Case-control studies - These studies
provide the relative risk estimates. A
case-control study from Agra, India, in-

eluded three categories of OSF patients


(15). Considering only 13 cases with
definite palpable fibrous bands (group
III), the relative risk of this condition
among areca nut chewers was computed
to be 43.8 (/'<0.01) (21). In a Taiwanese study of 35 cases and 100 controls,
SHIAU & KWAN (26) observed a high
correlation between this condition and
areca nut chewing. In an Indian study
of 60 cases and 60 controls, SINOR et al.
(21) reported a relative risk of 109.6 for
all forms of areca nut chewing, 106.4
for chewing mawa and 780.0 for the
combined use of mawa and betel quid.
In a recent study of 157 cases and
157 controls from Pakistan, MAHER et
al. (22) observed that those who chewed
areca nut in some form had a substantially higher relative risk (RR 94) compared to those who did not chew areca
nut. Areca nut chewing alone showed
the highest relative risk of 154, pan
chewing with tobacco the next highest
(RR 64), and the RR for chewing without tobacco was 32. The attributable
risk for chewing areca nut products as
compared to no chewing in the population was 98%.
Dose-response relationship - The relationship between the degree of exposure

Table 1. Distribution of large series of OSF cases according to gender ratio and frequency of
areca nut chewing

M:F

% with
areca nut
chewing habit

20
41
64
21
85
46
25
104
40
63
33
65
30

NA
0.9:1
0.9:1
NA
NA
0.6:1
1.5:1
2.1:1
1.6:1
0.3:1
0.1:1
NA
1.5:1

100%
NA
31%
NA
NA
NA
84%
34%
80%
67%
55%
71%
80%

0.4:1
1.2:1
29.0:1

100%
100%

21

64
24
60

22

157

23

18
115

Ref.
no.

Author(s)
India
LAL (1953)

7
8

JOSHI(1953)
DESA (1954)
SHARAN (1959)
SHIRAT & KHANOLKAR

(1962)
RAO (1962)
PINDBORG et al. (1964)
WAHI et al (1968)
MANI & SINGH (1968)
PINDBORG et al (1968)+
MEHTA et al (1972)
ABROL (1975)
AKBAR (1976)
BRONSLE et al. (1986)
ERNAKULAM
PUNE
SINOR et al (1990)

10
11

12
13
14

15
16
1
17
18
19
20

98%

Pakistan
MAHER

et al. (1994)

1.0:2.3

99%

South Africa
RANDERIA (1977)
SEEDAT (1985)+ +
SEEDAT & VAN WYK

(1988)

24
25

71

18.0:0
0.1:1
0.01:1

100%
100%
100%

44

0.2:1

100%

UK
CANNIFF

et al (1986)

NA, Not available


+From five areas of India
++Only referred cases included here

27

148

MURTI et al.

and the risk of a disease is an important


criterion for causal inference. In the
case-control study from India referred
to earlier (21), the relative risk increased
with the duration as well as the frequency of the areca nut chewing habit.
In a bivariate analysis of the duration
and frequency of the habit, the risk of
OSF showed a clear dose-response relationship (21).
In the study from Pakistan (22), relative risks increased with the increase in
the frequency and duration of the habit,
although not consistently. The authors
opined that the frequency of areca nut
chewing was more important than the
duration of the habit.
While the Indian (21) and Pakistani
(22) studies demonstrated a dose-response relationship, in a South African
study (25) there was a significant difference between the median duration of
areca nut chewing among those with the
disease (16 years) and those without the
disease (26 years). Although these
findings are apparently opposed to the
hypothesis of a dose-response relationship, the difference was not adjusted for
age.
Cross-sectional studies - These provide the prevalence of OSF among
chewers and non-chewers of areca nut,
and also compare the frequency of this
habit between the affected individuals
and the general population. The prevalence of this condition in Ernakulam
district, Kerala, India was 894 per
100,000 among areca nut chewers as
compared to 31 per 100,000 in non-users of areca nut (53). The two cases
detected among non-chewers were really among past chewers, so essentially
the prevalence among non-chewers of
areca nut was zero.
In four cross-sectional studies from
India (17) and South Africa (25, 54, 55)
there was an over-representation of the
areca nut chewing habit in the affected
subjects as compared to that in the general population (Table 2).
Prospective studies - These are reported only from India where, over a
10-yr period, large cohorts of individ-

uals with and without areca nut chewing habits have been foUowed-up annually to obtain the incidence rates of
OSF (43). There were a substantial
number of person-years of observation
among non-users of areca nut, including smokers, but all new cases of this
condition developed among areca nut
chewers (43).
Intervention studies - An intervention
study has shown a decrease in the risk
for OSF as a result of education against
chewing habits (56, 57). MURTI et al.
(56) demonstrated a fall in the incidence
of OSF from 21.3 per 100,000 personyears among men in the control cohort
to 8.3 in the intervention cohort, and
from 45.7 to 29.0 among women in the
control cohort (the cohort which was
subjected to habit intervention). This
reduction was not statistically significant because of the small number of
incidence cases; nevertheless, it highlighted the decreased risk with the reduction in areca nut habit.
Regional variations - The prevalence
and the frequency of OSF vary considerably in different areas in India (1,
58-62). It has been suggested that the
arecoline content of the areca nut varies
from place to place in India and perhaps this may have some influence on
the prevalence rate (63).
Certain distinct clinical observations
in India also support the etiologic role
of areca nut in OSF. For example,
BHONSLE et al. (20) demonstrated that
in Pune district, Maharashtra, this condition affected the posterior one-third
of the buccal mucosa, soft palate, the
uvula, and retromolar areas significantly more often than in Ernakulam
district, Kerala; on the other hand the
tongue, floor of the mouth and the hard
palate were not involved in Pune. The
average age of patients in Pune was
lower than in Ernakulam. In Pune 67%
chewed only areca nut, while in Ernakulam 77% chewed areca nut as an ingredient of betel quid with tobacco and
the remainder both chewed areca nut
and smoked tobacco. A plausible explanation for these regional differences is

Table 2. Distribution of areca nut chewing habits in cases and the general population
Areca nut habit
Author(s)
SHEAR et al. (1967)
DocKRAT & SHEAR (1969)
MEHTA et al. (1972)
SEEDAT & VAN WYK (1988)

Ref.
no.
54
55
17
25

Population
1000
1200
101761
2058

Cases

Population
%

Cases
%

5
7
33
63

12.3
22.0
2.1
9.0

100.0
100.0
52.1
100.0

that when individuals chew areca nut


without tobacco, as in Pune, they generally swallow the juice, thus exposing
the posterior part of the oral mucosa
(such as the posterior one-third of the
buccal mucosa, soft palate and uvula)
to areca nut contents much more than
the anterior parts. In Ernakulam, areca
nut is chewed in betel quid with tobacco, therefore the quid and the juice are
held for a longer time and are spat out
when they become bland. This results in
a more generalized contact of the quid
with the oral mucosa, perhaps leading
to its generalized involvement in OSF.
Animal experiments and tissue-culture
studies

While epidemiologic studies have identified areca nut as the primary etiologic
agent involved in this condition, animal
experiments have investigated the effect
of arecohne on submucosal collagen
and tissue-culture studies have explored
the action of areca nut extracts and specific alkaloids on human fibroblasts.
As part of the attempt at induction
of submucous fibrosis in animal models
SIRSAT & KHANOLKAR (64) painted the
palates of 27 Wistar rats with arecoline,
an active principle of areca nut {Areca
catechu). The submucosal collagen
showed altered staining similar to that
seen in human OSF only in two rats,
and therefore the investigators opined
it was improbable that arecoline per se
played any part in the causation of
human OSF. They pointed out, however, that tissue changes brought about
in animal systems by a test substance
cannot be identically correlated to
those in man.
Areca nut alkaloids yield powerful
carcinogenic nitrosamines (65). The carcinogenicity of areca nut has been investigated in many animal experiments,
with conflicting results (49), but there
was no mention of any changes suggestive of OSF in these studies.
In contrast to the above observation
from experimental studies, tissue-culture experiments using human fibroblasts suggested that areca nut is involved in the pathogenesis of OSF. CANNIFF & HARVEY (66) demonstrated that
ethanohc extracts of three varieties of
areca nut stimulated collagen synthesis
to the extent of 170% over that in control cultures. HARVEY et al. (67) studied
the interaction of arecoline and arecaidine with human fibroblasts. They found
that although both alkaloids stimulated
collagen synthesis, the influence of are-

Etiology of submucous fibrosis 149


caidine was more pronounced and it
was concentration-dependent. The synthesis of collagen stimulated by arecoline was time-dependent, peaking at 24
h. Both alkaloids stimulated proliferation of fibroblasts, although at the 100
g level arecoline was cytotoxic. Fibroblasts metabolized [^^]-arecoline to
P"]-arecaidine and various esters of
arecaidine. The metabolism of arecoline
to arecaidine was considered important
and necessary, as the latter was a more
potent stimulator of fibroblast prohferation and collagen synthesis.
Interestingly, it was suggested that
the addition of slaked lime to areca nut
in pan (betel quid) hydrolyses arecoline
to arecaidine (67). This means that the
hydrolysis of arecoline could occur in
the saliva as well as in fibroblasts. It was
suggested that the inflamed oral mucosa
has enhanced permeability to arecoline
and arecaidine.
In-vitro comparison of human fibroblasts from the normal and OSF
tissue did not reveal any intrinsic differences in their response to arecoline,
although OSF fibroblasts did show a
shghtly higher basal rate of collagen
synthesis (68).
The large quantities of tannins and
the flavanoid catechin present in the
areca nut do not appear to take part in
collagen synthesis. However, they form
cross-hnkages between the collagen
peptide chain, inhibiting collagen degradation by collagenase (69) and resulting in the accumulation of collagen
in OSF
Genetic susceptibiiity

The possibihty of genetic susceptibihty


for this condition has been probed by
CANNIFF et al. (27). They performed
HLA tissue typing and observed that
the frequencies of HLA AlO, DR3, and
DR7 in their sample of 44 patients were
significantly different from the ethnically-, regionally-, and age-matched control group. Further analysis of the
haplotypic pairs A10/DR3, A10/B8 and
B8/DR3 showed an increased frequency
in the patients, although this was not
statistically significant for the latter two
pairs. These observations were interpreted to imply a possible genetic susceptibility to the action of extrageneous
factors such as areca alkaloids and tannins.
The famihal occurrence of this condition has also been reported from India
(21) and South Africa (24). In the Indian study of 60 cases, seven individuals

were siblings from three families. The


occurrence of OSF among individuals
without areca nut chewing habits (3739, 70-73) has also been thought to be
due to genetic factors (73).

Autoimmunity

Suspicion of an autoimmune explanation for OSF stems from certain similarities of this condition with other collagen disorders, namely scleroderma,
which is presumed to have an autoimmune pathogenesis (74, 75). Scleroderma is characterized by induration and
fixation of the skin to the deeper subcutaneous tissues. Oral mucosal involvement, which occurs rarely, is marked by
thinness of the lips, stiffening of the
tongue, difficulty in eating and inability
to open and close the mouth properly.
Because of the similarities of clinical
features between OSF and scleroderma,
Su (9) felt that his cases represented
oral scleroderma.
A link between scleroderma and OSF
has also been suspected on the basis of
the similarity of histologic characteristics. SIRSAT & KHANOLKAR (76) observed refractile eosinophilic material
and a marked increase in PAS-positive
material with metachromasia in the
ground substance in OSF. These characteristics were similar to the histochemical reaction indicative of the presence of fibrinoid in a number of connective tissue disorders involving dense
collagen prohferation. The ultrastructural changes in this condition were also
similar to those seen in rheumatoid arthritis and scleroderma.
It became apparent that DR antigen,
which indicates an autoimmune basis of
a disease, was associated with scleroderma (74, 75). Interestingly, CANNIFF et al.
{11) reported an increase in DR3 antigen in OSF and also the presence of serum immunoglobulins and autoantibodies. In view of the female bias, the
age of onset of this condition, and other
immunologic and genetic findings, the
authors felt that OSF, like scleroderma,
could have an autoimmune basis.
In a South African study the possible
influence of autoimmunity was investigated among 105 patients by examining
their sera for the presence of antibodies
to parietal cells and nuclear proteins
(24). About 18% of the patients exhibited serum parietal cell antibodies,
which was higher than in the general
population (5-8%). The author postulated that betel nut alkaloids may act

as haptens which may produce antibodies to parietal cells. Furthermore, because of the similarities between the betel nut protein and parietal cell protein,
antibodies produced to betel nut antigens may cross-react with parietal cell
protein. There was, however, no evidence of gastric mucosal involvement in
this disease.

Comments

There are some inherent difficulties in


assessing data reported over a long time
period, from 1953-94, by many workers
with varied concepts concerning the etiology and clinical criteria for OSF. For
example, not all investigations have included the presence of palpable fibrous
bands among the diagnostic criteria,
nor have the criteria for completeness
of recording areca nut chewing always
been clear.
The importance of having palpable
fibrous bands as a diagnostic criterion
for submucous fibrosis can be better appreciated from re-analysis of the data
on 104 cases of OSF reported by WAHI
et al. (15). In this study, among 13 patients in group III, one of the inclusion
criteria was palpable fibrous bands,
while patients were included in groups
I and II on the basis of other symptoms
such as a burning sensation. The relative risk for areca-nut chewing, including tobacco chewing, for group III was
43.8, but the similar relative risk for the
remaining two groups combined was
1.0.
Although chilli consumption, nutritional deficiencies and autoimmune
background have been thought to be involved in the pathogenesis of OSF, the
evidence is too circumstantial to be of
any relevance.
Concerning genetic susceptibility,
there is only one study so far indicating
that it renders the mucosa more prone
for irritants like areca nut chewing (27).
This study used now out-dated serological methods. Further studies utilizing
more recent immunochemical techniques are desirable for understanding
this aspect of the disease. Similarly, the
occurrence of OSF among those without an areca nut habit has been suspected to be due to spontaneous genetic
susceptibihty (73); this viewpoint also
needs further elucidation.
In contrast to other suspected factors, considerable data has accrued
over the years in support of the etiologic role of areca nut in this condi-

150 MuRTi et al.


tion. They derive from a variety of epickmiologic studies providing consistency, strength, and a dose-response
relationship as well as from tissue-culture studies (66, 67). Tissue-culture
studies involving cell lines from human
fibroblasts have reproduced connective
tissue disorders, as the fibroblasts retain their phenotypes in culture and
possess many of their properties seen
in vivo (67). Collectively, these two approaches have demonstrated that areca
nut is the most likely factor in the etiopathogenesis of OSF. In the light of
this information, the pathogenesis of
OSF can be suggested to consist of
stimulation of fibroblasts by the areca
nut constituents, notably the alkaloids,
which results in their phenotype alteration as well as increased coUagenogenesis. The large quantities of tannins
and the flavanoid catechin in the areca
nut inhibit collagen degradation by
collagenase (69), resulting in the accumulation of collagen; genetic susceptibility perhaps accentuates the pathogenesis. The chronic inflammatory cell
infiltrate often present in the submucosal layer is also believed to stimulate
fibroblast proliferation and collagen
synthesis through release of factors
like IL 1 (interleukin 1) (68). In recent
times the role of cytokines of inflammatory cell origin in stimulating fibroblast proliferation is receiving attention. In that context it would be of
interest to investigate whether the inflammatory cells in submucous fibrosis
play a role in its pathogenesis.
Some investigators have studied the
ultrastructural changes of collagen in
submucous fibrosis (76-78). BINNIE &
CAWSON (77) reported fine (immature)
fibrils in the solitary sample they
studied and felt that these probably represented embryonic collagen and that
the pathogenesis involves defects in the
polymerization and maturation of collagen. In contrast, more recently VAN
WYK et al. (78) studied 11 tissue samples from submucous fibrosis and 15
controls and reported that while there
was excessive deposition of collagen, especially Type I, the fibrils were morphologically normal.

the use of areca nut products, including


those without tobacco, through public
education. This is essential because of
the increasing and widespread use of
areca-nut preparations like pan masala
(betel quid mixtures) by all classes of
people (50). These products are now
commercially manufactured and marketed in attractive foil packs and tins.
Carrying a pan masala tin has become
a status symbol and offering pan masala
is accepted as implying hospitality and
equality. There are no data on the
prevalence of its use, but its popularity
can be gauged by the fact that the Indian market for pan masala is worth Rs.
2000 million (US$ 116 million). These
products are also exported to many
countries and OSF is reported among
those who use them (27). There are already indications in India of an
increased occurrence of OSF due to this
product and it is likely to reach an
alarming proportion in the near future.
Its implication is that oral cancer occurrence would also increase correspondingly. Encouragingly, primary
prevention has been demonstrated to be
practicable (56, 57) and useful in reducing the incidence of OSF (56) and therefore efforts must be initiated in that direction.
Acknowledgements - This study was supported by funds from the Indo-US Fund Research agreement No. N-406-645.

References
1. PiNDBORG JJ,

MEHTA F S , GUPTA

PC,

Prevalence of oral submucous fibrosis among 50,915 Indian


villagers. Br J Cancer 1968; 22: 646-54.
2. PiNDBORG JJ. Oral cancer and precancer.
Bristol: John Wright & Sons, 1980.
DAFTARY D K .

3. PiNDBORG JJ, MURTI PR, BHONSLE R B ,


GUPTA PC, DAFTARY DK, MEHTA FS.

Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 1984:


89: 270-4.
4. MuRTi PR, BHONSLE RB, PINDBORG JJ,
DAFTARY DK,

GUPTA PC, MEHTA FS.

Malignant transformation rate in oral


submucous fibrosis over a 17-year
period. Community Dent Oral Epidemiol
1985: 13: 340-1.
5. GUPTA PC, BHONSLE RB, MURTI PR,
DAFTARY DK, MEHTA FS, PINDBORG JJ.

Control of OSF

So far, there does not seem to be any


satisfactory treatment for OSF (31, 72).
As areca nut has been identified as an
etiologic agent, it is amenable to primary prevention. The preventive measures should be in the form of curbing

An epidemiologic assessment of cancer


risk in oral precancerous lesions in India
with special reference to nodular leukoplakia. Cancer 1989: 63: 2247-52.
6. SCHWARTZ J. Atrophia idiopathica
(tropica) mucosae oris. Demonstrated at
the 11th International Dental Congress,
London, July 1952.

1. LAL D. Diffuse oral submucous fibrosis.


J All-India Dent Assoc 1953: 26: 1-3.
8. JosHi SG. Submucous fibrosis of the palate and the pillars. Indian J Otolaryngol
1953: 4: 1-4.
9. Su I-PiN. Idiopathic scleroderma of the
mouth. Arch Otolaryngol 1954: 59: 3302.
10. DESA J V Submucous fibrosis of the palate and cheek. Ann Otol Rhinol Laryngol
1957:66: 1143-59.
11. SHARAN J. Histopathological observations on cases of submucous fibrosis of
the oral cavity. Indian J Pathol Bacteriol
1959: 2: 150-2.
12. SiRSAT SM, KHANOLKAR V R . Submucous fibrosis of the palate and pillars of
the fauces. Indian J Med Sci 1962: 16:
189-97.
13. RAO A B N . Idiopathic palatal fibrosis. Br
J Surg 1962: 50: 23-5.
14. PINDBORG JJ, CHAWLA T N , SRIVASTAVA
AN, GUPTA D, MEHROTRA M N . Clinical

aspects of oral submucous fibrosis. Acta


Odontol Scand 1964: 22: 679-91.
15. WAHI P N , KAPUR V L , LUTHRA UK, SRIVASTAVA MC. Submucous fibrosis of the

oral cavity. 2. Studies on epidemiology.


Bull WHO 1966: 35: 793-9.
16. MANI N J , SINGH B. Studies on oral submucous fibrosis. 1. Clinical aspects. / Indian Acad Dent 1968: 9: 27-36.
17. MEHTA FS, GUPTA PC, DAFTARY DK,
PINDBORG JJ, CHOKSI S K . An epidemio-

logic study of oral cancer and precancerous conditions among 101,761 villagers
in Maharashtra, India. Int J Cancer
1972: 10: 134^1.
18. ABROL B M . Clinicopathological, biochemical and immunological studies in
syndrome of idiopathic oral fibrosis
(submucous fibrosis). Bombay Hosp J
1975: 19: 50-61.
19. AKBAR M . Oral submucous fibrosis - a
clinical study. J Indian Dent Assoc 1976:
48: 365-73.
20. BHONSLE RB, MURTI PR, DAFTARY DK,

et al. Regional variations in oral submucous fibrosis in India. Community Dent


Oral Epidemiol 1987: 15: 225-9.
21. SiNOR PN, GUPTA PC, MURTI PR, et al.
A case-control study of oral submucous
fibrosis with special reference to the etiologic role of areca nut. / Oral Pathol
Med 1990: 19: 94-8.
22. MAHER R, LEE AJ, WARNAKULASURIYA
KAAS, LEWIS J A , JOHNSON N W . Role of

areca nut in the causation of oral submucous fibrosis - a case-control study in


Pakistan. J Oral Pathol Med 1994: 23:
65-9.
23. RANDERIA J D . Oral submucous fibrosis
as a precancerous lesion. J Dent Assoc
S Afr 1982: 37: 521-6.
24. SEEDAT H A . Oral submucous fibrosis in
Durban, Natal: a study of its epidemiology, aetiology and morphological
features. Thesis. Stellenbosch, South
Africa. University of Stellenbosch,
1985.
25. SEEDAT HA, VAN WYK CW. Betel chew-

Etiology of submucous fibrosis 151


ing and dietary habits of chewers without and with submucous fibrosis and
with concomitant oral cancer. South Afr
MedJl98H:14: 572-5.
26. SHIAU YY, KWAN HW. Submucous fibrosis in Taiwan. Oral Surg Oral Med
Oral Pathol 1979: 47: 453-7.
27. CANNIFF JP, HARVEY W, HARRIS M . Oral
submucous fibrosis: its pathogenesis and
management. Br Dent J 1986: 160: 42934.
28. WARNAKULASURIYA S. Semi-quantitative
clinical description of oral submucous
fibrosis. Ann Dent 1987: 46: 18-21.
29. LAY KM, SEIN K , MYINT A, Ko SK,
PINDBORG JJ. Epidemiologic study of

6000 villagers of oral precancerous


lesions in Bilugyun: preliminary report.
Community Dent Oral Epidemiol 1982:
10: 152-5.
30. CHOUDHRY CR,

31.

32.

33.

34.

BHUIYAN M , MOHIDU-

ZAMMAN M. Submucous fibrosis in Bangladesh.


PINDBORG JJ, SIRSAT SM. Oral submucous fibrosis. Oral Surg Oral Med Oral
Pathol 1966: 22: 764-79.
BARMES D, DUKE P. Submucous fibrosis.
Papua New Guinea Med J 1975: 18: 6670.
MANI NJ, KIM HW, SASTRY KARH.
Oral submucous fibrosis in a Saudi female. Ann Dent 1985: 44: 12-3.
FAHMY MS. Submucous fibrosis. A premahgnant oral disease. Case report. J
Kuwait Med Assoc 1972: 6: 23-8.

35. HAMNER JE, III,

LOONEY PD, CHUSED

TM. Submucous fibrosis. Oral Surg Oral


Med Oral Pathol 1974: 37: 412-21.
36. HAYES PA. Oral submucous fibrosis in a
4-year old girl. Oral Surg Oral Med Oral
Pathol 1985: 59: 475-8.
37. LEMMER J, SHEAR M . Oral submucous
fibrosis: a possible case in a person of
Caucasian descent. Br Dent J 1967: 122:
343-6.
38. SIMPSON W. Submucous fibrosis. Br J
Oral Surg 1969: 6: 196-200.
39. LASKARIS G, BOVOPOULOU O, NICOLIS G,

Oral submucous fibrosis in a Greek female. Br J Oral Surg 1981: 19: 197-201.
40. SIRSAT SM, KHANOLKAR VR. Submucous fibrosis ofthe palate in diet-preconditioned Wistar rat. Arch Pathol 1960:
70: 171-9.
41. PINDBORG JJ, SINGH B. Formation of
vesicles in oral submucous fibrosis. Acta
Pathol Microbiol Scand 1964: 62: 562-6.
42. SIRSAT SM, PINDBORG JJ. Subepithelial
changes in oral submucous fibrosis. Acta
Pathol Microbiol Scand 1967: 70: 16173.
43. GUPTA PC, MEHTA FS, DAFTARY

DK,

et al. Incidence rates of oral cancer and


natural history of oral precancerous
lesions in a 10-yr follow-up study of Indian villagers. Community Dent Oral
Epidemiol 1980: 8: 287-333,
44. NAGABHUSHAN M , BHIDE SV Mutagenicity of chillie extract and capsaicin in
short term tests. Environ Mutagen 1985:
7: 881-8.

45.

SV. Carcinogenic potential of


some Indian tobacco products. In: GUP-

BHIDE

TA PC, HAMNER JE, III, MURTI PR,

eds.

Control of tobacco-related cancers and


other diseases. Bombay. Oxford University Press, 1992. pp. 217-22.
46. NOTANI PN. Role of diet and alcohol in
tobacco-related cancer at sites in the upper aerodigestive tract in an Indian
population. In: GUPTA PC, HAMNER JE,
III, MURTI PR, eds. Control of tobaccorelated cancers and other diseases. Bombay. Oxford University Press, 1992. pp.
149-55.
47. RAMANATHAN K . Oral submucous fibrosis - an alternative hypothesis as to
its causes. Med J Malaysia 1981: 36:
243-5.
48. ARJUNGI KN. Areca nut. A review. Arzneimittelforschung 1976: 26: 951-6.
49. INTERNATIONAL AGENCY FOR RESEARCH

ON CANCER. IARC monographs on the


evaluation of the carcinogenic risk of
chemicals to humans. Vol. 37. Tobacco
habits other than smoking: betel-quid and
areca nut chewing; and some related nitrosamines. Lyon: International Agency
for Research on Cancer, 1985.
50. BHONSLE RB,

MURTI PR,

GUPTA PC.
In: GUPTA PC,

Tobacco habits in India.


HAMNER JE, III, MURTI PR, eds. Control
of tobacco-related cancers and other
diseases. Bombay. Oxford University
Press, 1992. pp. 25-46.
51. PINDBORG JJ, MURTI PR, BHONSLE RB,
GUPTA PC. Global aspects of tobacco

use and its implications for oral health.


In: GUPTA PC, HAMNER JE, III, MURTI

PR, eds. Control of tobacco-related cancers and other diseases. Bombay. Oxford
University Press, 1992. pp. 13-9.
52. SiNOR PN, MURTI PR, BHONSLE RB,
GUPTA PC. Mawa chewing and oral submucous fibrosis in Bhavnagar, Gujarat,
India. In: GUPTA PC, HAMNER JE, III,
MURTI PR, eds. Control of tobacco-related cancers and other diseases. Bombay.
Oxford University Press, 1992. pp. 10712.
53. MEHTA FS, PINDBORG JJ, HAMNER JE,

III, et al. Oral cancer and precancerous


conditions in Indian rural populations,
1966-69, Copenhagen, Munksgaard,
1971,
54. SHEAR M , LEMMER J, DOCKRAT I. Oral
submucous fibrosis in South African Indians. An epidemiologicai study. South
Afr J Med Sei 1967: 32: 41-6.
55. DOCKRAT 1, SHEAR M . Oral submucous
fibrosis in Natal. In: CAHN L, ed. 4th
Proceedings of the International Academy of Oral Pathology. New York, Gordon & Breach, 1969. pp. 57-63.
56. MURTI PR, GUPTA PC, BHONSLE RB,
DAETARY DK, MEHTA FS, PINDBORG JJ.

Effect on the incidence of oral submucous fibrosis of intervention in the areca


nut chewing habit. J Oral Pathol Med
1990: 19: 99-100.
57. GUPTA PC,

MEHTA FS, PINDBORG

JJ,

et al. Primary prevention trial of oral

cancer in India: a 10-year follow-up


study. J Oral Pathol Med 1992: 21: 4339.
58. PINDBORG JJ. Frequency of oral submucous fibrosis in North India. Bull WHO
1965: 32: 748-50.
59. PINDBORG JJ, CHAWLA TN, MISRA RK,
NAGPAUL RK, GUPTA VK. Frequency

of oral carcinoma, leukoplakia, leukokeratosis, leukoedema, submucous fibrosis, and lichen pianus in 10,000 Indians
in Lucknow, Uttar Pradesh, India: preliminary report. J Dent Res 1965: 44: 615
(only).
60. PINDBORG JJ, KALAPESI HK, KALE SA,
SINGH B, TALEYARKHAN BN. Frequency

of oral leukoplakia and related conditions among 10,000 Bombayites: preliminary report. J All-India Dent Assoc 1965:
37: 228-9.
61. PINDBORG JJ, BHAT M , DEVANATH KR,
NARAYANA HR, RAMACHANDRA S. Fre-

quency of oral white lesions among


10,000 individuals in Bangalore, South
India: preliminary report. Indian J Med
Sei 1966: 20: 349-52.
62. ZACHARIAH J, MATHEW B, VARMA NAR,
IQBAL AM, PINDBORG JJ. Frequency of

oral mucosal lesions among 5000 individuals in Trivandrum, South India: preliminary report. / All-India Dent Assoc
1966: 38: 290-4.
63. AwANG MN. Estimation of arecoline
contents in commercial areca (betel) nuts
and its relation to oral precancerous
lesions. Singapore Med J 1986: 27: 31720.
64. SIRSAT SM, KHANOLKAR VR. The effect
of arecoline on the palatal and buccal
mucosa of the wistar rat. An optical and
electron microscopic study. Indian J Med
Sei 1962: 16: 198-202.
65. HOFFMANN D, RIVENSON A, PROKOPCZYK B, BRUNNEMANN KD, CARMELLA
SG, HOFFMANN I. Advances in tobacco

carcinogenesis. I. Smokeless tobacco and


betel quid. In: GUPTA PC, HAMNER JE,
III, MURTI PR, eds. Control of tobaccorelated cancers and other diseases. Bombay. Oxford University Press, 1992. pp.
193-204.
66. CANNIFF JP, HARVEY W The aetiology of
oral submucous fibrosis: the stimulation
of collagen synthesis by extracts of areca
nut. Int J Oral Surg 1981; 10 (Suppl):
163-7.
67. HARVEY W, SCUTT A, MEGHJI S, CANNIFF JP. Stimulation of human buccal

mucosa fibroblasts in vitro by betel-nut


alkaloids. Arch Oral Biol 1986: 31: 459.
68. MEGHJI S, SCUTT A, HARVEY W, CANNIFF JP. An in-vitro comparison of

human fibroblasts from normal and oral


submucous fibrosis. Arch Oral Biol 1987:
32: 213-5.
69. KuTTAN R, DoNNELY PV, Di FERRANTE
N. Collagen treated with (+) catechin
becomes resistant to the action of mammalian collagenase. Experientia 1981:
37: 221-3.

152

MURTI et al.

70. PAISAT DK. Oral submucous fibrosis. Int


J Oral Surg 1981: 10: 307-12.
71. McGuRK M, CRAIG GT. Oral submucous fibrosis: two cases of malignant
transformation in Asian immigrants to
the United Kingdom. Br J Maxillo-fac
Surg 1984: 22: 56-64.
72. PINDBORG JJ. Oral submucous fibrosis: a
review. Ann Acad Med 1989: 18: 603-7.
73. SEEDAT HA, VAN WYK CW. Submucous
fibrosis in non-betel nut chewing subjects. J Biol Buccale 1988: 16: 3-6.

74. KALLENBBERG CGM, VAN DER VOORTBEELEN JM, D'AMARO J. THE TH.

Sclroderma: increased frequency of B8/


DR3 in scleroderma and association of
the haplotype with impaired cellular immune response. Clin Exp Immunol 1981:
43: 478-85.
75. WHITESIDE TL, MEDSGER TA, JR, ROD-

NAN GP. HLA DR antigens in progressive systemic sclerosis (scleroderma).


J Rheumatol 1983: 10: 163-7.
76. SIRSAT SM, KHANOLKAR VR. A histo-

chemical and electron microscopic study


of submucous fibrosis of the palate. /
Pathol Bacteriol 1957: 73: 439-42.
77. BiNNiE WH, CAWSON RA. A new ultrastructural finding in oral submucous
fibrosis. Br J Dermatol 1972: 86: 28690.
78. VAN WYK CW,

SEEDAT HA,

PHILLIPS

VM. Collagen in submucous fibrosis: an


electron microscopic study. / Oral Pathol Med 1990: 19: 182-7.