Professional Documents
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Oral Pathology&Meciidiie
ISSN 0904-2512
Review article
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.
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.
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
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-
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)
27
148
MURTI et al.
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
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-
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
References
1. PiNDBORG JJ,
MEHTA F S , GUPTA
PC,
Control of OSF
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,
31.
32.
33.
34.
BHUIYAN M , MOHIDU-
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,
45.
BHIDE
eds.
MURTI PR,
GUPTA PC.
In: GUPTA PC,
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,
JJ,
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-
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
152
MURTI et al.
74. KALLENBBERG CGM, VAN DER VOORTBEELEN JM, D'AMARO J. THE TH.
SEEDAT HA,
PHILLIPS