Osmf

2011

Pathogenesis of Oral Submucous Fibrosis
Relationship to Risk Factors Associated With Oral Cancer
Radhakrishna Pillai, PhD,*,t Prabha Balaram, PhD,t
and Kannan Sankara Reddiar, MSct$

Oral submucous fibrosis (OSF) is a chronic disease of the may lead to relative loss of auditory acuity because of
oral mucosa characterized by inflammation and a pro- stenosis of the opening of the Eustachian tube. In ad-
gressive fibrosis of the lamina propria and deeper con- vanced cases, there may be severe trismus, and the to-
nective tissues. It is a condition predominantly seen tally inelastic mucosa is forced against the teeth, leading
among people of Indian origin, and an epidemiologic sur- to chronic ulceration and subsequent infection.
vey done a decade ago showed no less than 250,000 cases
In many cases, the fibrous tissue can be seen to
in India, a figure that must have increased sharply. OSF
is a condition with a high risk of malignant transforma-
extend from the anterior pillars into the soft palate as a
tion; to date, no conclusive etiologic agent has been iden- delicate reticulum of interlacing white strands that later
tified, although plenty of data have been generated on become confluent. The cheeks have a mottled marble-
various aspects of the disease. These include genetic, car- like mosaic appearance, with normal reddish mucosa
cinogenic, immunologic, viral, nutritional, and autoim- intermingling with depigmented diseased mucosa. The
mune possibilities, all of which also have been impli- floor of the mouth becomes pale and thickened, the
cated in the development of oral cancer. This article re- tongue becomes reduced in size and motility, and bands
views existing evidence on the pathogenesis of OSF and of encircling collagen distort the lips. If the fibrosis ex-
its relation to oral cancer and suggests a possible multi- tends down to the esophagus, the patient has progres-
factorial model to explain the disease process. Cancer sive dysphagia.
1992; 69:2011-2020.
Histologically, OSF is characterized by juxtaepithe-
lial fibrosis, along with atrophy or hyperplasia of the
Oral submucous fibrosis (OSF)is a chronic oral mucosal overlying epithelium, keratinizing metaplasia, and ac-
condition that occurs predominantly among Indians cumulation of hyalinized collagen beneath the base-
and people of Indian origin living outside India, occa- ment membrane with a progressive loss of vascularity.
sionally in other Asians, and sporadically in Europeans. Often, a variable infiltration of the lamina propria with
With prevalence rates in India from 0.2% to 1.2%, an chronic inflammatory cells also is e ~ i d e n t (Figs. 1, 2,
~-~
epidemiologic survey done a decade ago indicated no and 3).
less than 250,000 cases in the country.',' The possible precancerous nature of OSF first was
OSF is characterized by inflammation and a pro- described by Payma~ter,~ observed the onset of
who
gressive fibrosis of the lamina propria. The major pre- slowly growing squamous cell carcinomas in one-third
senting complaint is a progressive inability to open the of such patients. These observations were confirmed
mouth because of the accumulation of inelastic fibrous subsequently by Pindborg.' The cause of the disease,
tissue in the juxtaepithelial region of the oral mucosa, however, is still obscure. Hypersensitivity to chili and
along with concomitant muscle degeneration. Patients betel nuts and nutritional deficiencies all have been
describe a gradual onset of burning pain when eating suggested at various times to account for the pathogene-
spicy food that previously had caused no d i ~ t r e s sThe
.~ sis of the disease. However, it appears from current evi-
fibrosis also leads to difficulty in mastication, speech, dence that a combination of various factors could best
and swallowing and pain in the throat and ears. It also explain the pathogenesis of this unique condition.
These factors are discussed below, along with their re-
lationships to oral cancer.
From the *Department of FamiIy and Community Medicine,
University of Arizona, Tucson, Arizona; and the tRegiona1 Cancer
Centre, Trivandrurn, India. Genetic Alterations
4 Recipient of the Senior Research Fellowship of the Council for
Scientific and Industrial Research, India.
Address for reprints: Radhakrishna Pillai, PhD, Regional Cancer
Cancer researchers have amassed a great deal of data
Centre, Trivandmrn 69501 1, Kerala State, India. indicating that changes occur in the genetic control ap-
Accepted for publication July 15, 1991. paratus as cells progress to a malignant state. Almost all

2012 CANCER April 25, 2992, Volume 69, No. 8

Figure 1. Histologic changes in OSF showing atrophic epithelium Figure 3. Histologic changes in OSF showing atrophic epithelium
with loss Of rete Pegs and avascular hYalinized with loss of rete pegs and relatively avascular hyalinized collagen
extending downwards from the basement membrane (low-power extending downwards from the basement membrane (high-power
view; H & E, original magnification X75) view of the subepithelial region; H & E, original magnification
X300).

carcinogenic agents, whether physical (radiation),
chemical, or infectious (viruses), act as mutagens. They euploidy, detected with relative ease when flow
change the structure of the genetic material, producing cytometry is used.16
point mutations, deletions, insertions, or rearrange- Another finding closely allied to genetic abnormali-
m e n t ~ . ~ -The tendency for development of specific
" ties is the role of oncogenic viruses. These viruses carry
types of tumors has been noticed to be inherited in genes that can act in a dominant fashion to cause cells to
many situations, such as retinoblastoma, Cowden's undergo malignant transformation. lo Oncogenes or tu-
syndrome, Gardner's syndrome, and neurofibromato- mor-causing genes often are mutated genes derived
sis.ll-14 Specific chromosomal aberrations have been from apparently normal eukaryotic genes called proto-
found consistently in a number of tumors, such as Bur- oncogene^.'^ A large number of proto-oncogenes have
kitt's lymphoma, acute and chronic leukemias, and been identified in the human genome, whereas mu-
Wilm's t ~ m o r . These abnormalities are mostly trans-
'~ tated amplified and rearranged oncogenes have been
locations and deletions with breakpoints at specific lo- found in a wide variety of malignant It is
cations. Another chromosomal abnormality that ap- interesting that many of the chromosome deletions and
pears ubiquitous to most tumors is the presence of an- translocations characteristic of many cancers have
breakpoints near or at the proto-oncogene location^.^'
Although no one has precisely or even closely iden-
tified a genetic basis for OSF, it cannot be ruled out.
Although hypersensitivity to chili and betel quid often
is explained as a common factor in the development of
OSF, it is difficult to understand why the disease is not
seen in Mexico and South America, where the diet in-
cluding chili intake equals or even exceeds that in India
or the Far East. A proper genetic perspective thus is vital
to explain the condition.
Studies of invasive oral carcinomas have produced
substantial findings, which, if can be shown to also oc-
cur in OSF, could explain its pathogenesis. We had ex-
plained earlier the genetic abnormalities in oral cancers,
including altered oncogene expre~sion.'~ was evi-
This
dent by a fivefold to tenfold increase in amplification of
c-myc, N-myc, and Ki Y U S genes in 20% to 40% of biopsy
Figure 2. Histologic changes in OSF showing atrophic epithelium
with loss of rete pegs and relatively avascular hyalinized collagen specimens studied, with 56% showing amplification of
extending downwards from the basement membrane (high-Dower
x - 1
at least one of the oncogene^.'^ Studies on squamous
view of the epithelium; H & E, original magnification X300). cell carcinoma cell lines show considerable chromo-

Pathogenesis of OSFIPillai et al. 201 3

some triploidy and tetraploidy. One such study" found laboratory35 and others36 have shown high titers of
aberrations of chromosome 1 in nine head and neck anti-HSV1 antibody in patients with oral cancer and
carcinoma cell lines examined that mainly involved de- precancer, including OSF, compared with patients with
letions at lq21, lq32, lq13, or lp22. Two known proto- other cancers and normal controls, but efforts to isolate
oncogenes map to these areas. Transfection experi- or characterize virus-specific proteins from lesions were
ments also have been performed with the use of DNA u n s u c c e ~ s f u lHowever, as discussed in the next sec-
.~~
from squamous carcinomas of the head and neck. Al- tion, synergy between HSV, Candida, nutritional status,
though such experiments examining different types of and topical carcinogens may provide interesting clues
solid tumors have found that 15% to 30% of these tu- to the development of oral lesions. Human papilloma-
mors contained transforming gene^,'',^^,^^ studies with virus (HPV) infection also has been associated with cer-
DNA obtained from head and neck cancers indicate vical dysplasia and invasive ~arcinoma.~' relevance
Of
that nearly 100% may have been transforming to oral cancer is the demonstration of HPV structural
gene^.'^,'^ Transforming genes from head and neck antigens and Epstein-Barr virus in "hairy" leukoplakia,
cancers have been passed by transfection through four a condition seen in patients with acquired immune de-
generations of mouse fibroblast^,^^ which then go on to ficiency syndrome.39 Silvermann ef al. have shown a
produce fibrosarcomas when injected into nude mice.24 greater incidence of oral squamous carcinoma in pa-
Changes in DNA content and chromosome num- tients with acquired immune deficiency syndrome or
bers in head and neck carcinomas have been analyzed those at risk of getting it.40 Morphologic virus-like
in several studies.26-28 was seen that tumor cells
It changes have been seen in verrucous carcinoma^,^' and
mostly had an abnormally high DNA content, ranging Loning ef al. recently reported HPV antigens in oral
from 1.1 to 3.3 times the normal diploid In a No
papillomas and leukoplakia~.~' such study has been
unique study of another precancerous lesion of the oral done in OSF, but it could show valuable information
cavity, leukoplakia, Grassel-Pietrusky et ~ 1 . ' found be-
~ such as the possible role of viruses in oral precancers. Is
nign keratoses and mild to moderate leukoplakias to a defect in the immune system necessary for the viral
have normal diploid quantities of DNA, whereas le- infection? Or, vice versa, does viral infection cause im-
sions with dysplasia had aneuploid levels of DNA. mune defects? These questions are discussed further in
Studies such as the ones outlined thus are paving the section on immunology.
the way to a better understanding of the development
of precancers and cancers of the oral cavity. OSF is a Carcinogens
potent oral precancer and may have a strong genetic
link. These aspects may provide answers to the intrigu- One of the best-defined etiologic agents in the patho-
ing questions regarding the disease. genesis of most oral lesions, including OSF, is tobacco,
although it usually is associated with the areca nut
Infectious Agents Associated With Oral Cancer making up the betel quid. In one study, La1 reported
and Their Possible Role in OSF that all patients with OSF, without exception, had a
history of tobacco use.43In a cadaver study of oral epi-
Interest has been focused recently on the increase in thelium, Valentine ef ~ 1 used morphometry to relate
. ~ ~
chronic infections of the oral cavity and their role in the lingual epithelial thickness to levels of alcohol and to-
pathogenesis of premalignant lesions and cancer. Prom- bacco use. They found a reduction in the maturation
inent among the infectious agents postulated to have layer resulting mainly from cell shrinkage and con-
such a role are Candida and viruses. Clinically and ex- cluded that the changes were nonspecific reactions to
perimentally, candidiasis has been associated with epi- local toxic effects of tobacco and alcohol. Polycyclic aro-
thelial h y p e r p l a ~ i a . ~ It -also has been shown to be
~ ~l matic hydrocarbons are the main precarcinogens in to-
present in speckled leukoplakias and has been asso- bacco smoke. They are activated to ultimate carcino-
ciated with OSF.32 The development of precancers into gens in cells by microsomal complex enzymes com-
invasive malignant neoplasms also has been reported to monly referred to as aryl hydrocarbon hydroxylases.
be higher when the latter is associated with candid^.^^ It Making an important observation in this regard, Trell et
is not clear whether Candida has a definitive role in the found that patients with oral cancer had higher
pathogenesis of OSF or its subsequent malignant trans- aryl hydrocarbon hydroxylase inducibility compared
formation, although it has a definite role in nitrosamine with controls. Another type of carcinogen found in to-
production, as discussed later. bacco is N-nitrosonornicotine, which is the predomi-
Herpes simplex viruses (HSV) have long been asso- nant carcinogen found in chewing tobacco. "-nitro-
ciated with cancers: HSVl with lip and oral cancer and sonornicotine is produced by bacterial and enzymatic
HSV2 with uterine cervix cancer.34 Studies from our nitrosation of nicotine and can be found by reaction of


salivary nitrates with nornicotine. N-nitrosonornico- atrophy of the mucosa of the upper gastrointestinal
tine levels increased 44% when tobacco was mixed with tract in middle-aged women who were chronically ane-
saliva, and it is important to realize that the N-nitro- mic. The condition was further elaborated by Walden-
sonornicotine extracted from chewing tobacco with sa- strom and Kjellberg,60who showed the significance of
liva is approximately 1000 times that found in cigarette diminished iron stores and the absence of stainable
smoke.46These findings have direct relevance to condi- bone marrow iron. They introduced the term sidero-
tions such as OSF because these patients have histories penic dysphagia to describe this disease complex
of prolonged continuous tobacco chewing. known as the Paterson-Kelly syndrome or Plummer-
There remains, however, some disagreement as to Vinson syndrome. Additional studies,61,62 apart from
whether the tobacco component is in fact the main fac- confirming the importance of the syndrome in the de-
tor of concern in the development of OSF or if the entire velopment of carcinoma of the meso and hypopharynx,
betel quid is dangerous. In reviewing literature, Kha- showed that this also applied to the buccal mucosa,
dim47reported that the addition of tobacco to the betel tongue, and all levels of the esophagus. A number of
quid increased the risk from 4 (without tobacco) to as studies also have reported the development of single or
much as 29 with its addition. Atkinson et ~ l . , ~ however,
' multiple oral cancers in such patient^.^^-^^ The similari-
suggested that the possible etiologic agent may be lime. ties between OSF and sideropenic dysphagia were so
This idea is supported by the observation of an elevated evident that Ramanathan66suggested that OSF may be
oral cancer incidence related to endemic chewing habits considered the Asian analog of the Plummer-Vinson
in Malaysia and Papua New G ~ i n e a , ~ where it is
',~~ syndrome.
customary to use betel nut with lime but without to- Rennie et u1.67,68
have shown that, in human iron-
bacco. The incidence is contrastingly low in Afghanis- deficiency anemia and experimental iron deficiency in
tan and Nigeria, where tobacco is chewed without hamsters, quantitative histologic changes in the oral epi-
lime.50Taking into account these possibilities, we had thelium are demonstrable. The epithelium is atrophic,
suggested earlier51that the lime in the betel quid causes with a reduced maturation compartment but an in-
constant aberration of the oral mucosa, allowing direct creased keratinized compartment. Cell kinetic studies
access to the carcinogens. have shown increased cell production, indicating that,
Also of relevance to OSF is the role of the betel nut. despite the atrophy, the epithelial turnover is rapid.
It has been shown that betel nut extracts5' and, in partic- From this it can be presumed that there may be an in-
ular, the alkaloid component a r e ~ o l i n e ~ ~stimulate
can creased susceptibility to chemical carcinogens due to an
fibroblast proliferation and collagen synthesis in vitro. increased population of susceptible dividing cells and
The flavonoids and tannins from betel nut can stabilize also to a more permeable epithelium. An animal
collagen fibrils and render them resistant to degrada- showed that the development of carcinomas in rats
tion by collagenase. treated with a carcinogen was more rapid in iron- defi-
Most of the carcinogens involved in the malignant cient animals than normal animals.
transformation of the oral mucosa may be acting to- There is no doubt that iron is essential for overall
gether or synergistic to each other. Recent studies have integrity and health of epithelia of the digestive tract,
shown local synergistic effects between HSV infection and its importance may lie in its contribution to normal
and t o b a c ~ o .Yeasts have the capacity to produce
~~,~~ enzymes. Serious impairment of cell-mediated immune
carcinogens, mainly nitrosamines, from precursors and functions also has been found in iron-deficient pa-
could act in association with other carcinogen^.^^ This t i e n t ~Changes in the oral mucosa can occur before
.~~
has direct relevance to oral precancers when one con- significant alterations in erythrocyte morphologic char-
siders the high prevalence of oral infections in such acteristics or hemoglobin levels are observed.71It thus
people. appears that iron can have an important role in the
development of oral precancers, including OSF, and
Nutritional Factors their conversion to cancer.
Although most interest has been shown in the role
Iron metabolism is important in maintaining the health of iron, other nutritional factors also may be involved in
of the oral mucosa, and many disease states, including the pathogenesis of OSF. Deficiencies in folic acid, pyr-
cancers, are associated with iron depletion.57Iron defi- idoxine, and vitamin B1272,73 may be secondary to that
ciency may be the most common deficiency state in the of iron, and hence difficult to estimate. Also of great
world, affecting both affluent and developing coun- interest are the possible protective effects of certain nu-
tries. trients such as vitamin A and beta-carotene. Studies
In 1919, Paterson5' and Kelly59independently de- from India show that 76.2% of patients with oral and
scribed the symptom complex of chronic dysphagia and oropharyngeal cancers have subnormal levels of serum

Pathogenesis of OSF/PiJlai et al. 2015

vitamin A.74 similar study from Pakistan showed pa-
A totoxic rather than suppressor T-cells would contribute
tients with oral cancer to have significantly lower levels to an antitumor response.94However, criticism of this
of vitamin A and beta-carotene compared with normal concept stems from the overall skepticism of the im-
controls.75It is of interest that intervention trials with munosurveillance theory as a result of the apparent lack
beta-carotene and vitamin A in patients with oral pre- of antigenicity of malignant or potentially malignant
cancers have resulted in substantial regression of the cells. This would preclude any role for the immune sys-
lesion^.^^,^^ tem (apart from the NK-cell system). Nevertheless,
available evidence does indicate that immune effector
Immunologic Factors to be Considered in OSF cells recognize cancer cells as foreign and the malignant
transformation of oral precancers such as OSF may in-
A most obvious and significant element related to the volve the elicitation of a defective or inappropriate re-
ultimate development of cancer is the status of the im- sponse. An example would be the generation of a sup-
mune system. It has been shown that when immuno- pressor T-cell response rather than one by cytotoxic T-
suppression has been present for significant periods of cells.95 A decrease in the CD4/CD8 ratio among
time, the likelihood of a malignant tumor appearing is tissue-infiltrating cells in oral precancers, as was ob-
enhanced.78This may happen in naturally occurring im- served by Migliorati et is suggestive of this and
munosuppression or when immunosuppression is in- probably represents an imbalance in immunoregula-
duced artificially. The significant role of immunity is tion. Proliferation of suppressor cells rather than helper
becoming appreciated, especially with regard to the cytotoxic cells can lead to immunosuppression and con-
management and prognostication of many tumors. We sequent tissue damage. Evidence from murine and hu-
have conclusively shown immune defects in patients man ~ t u d i e sshows~suppressor cells to be distinct
~~, ~
with squamous cell c a r c i n ~ m a s ~ ~and~ indicated
,~ -~' from cytotoxic cells; the former are Ia positive, whereas
how this could be directly applicable to progno~is.~' We the latter are Ia negative. Most of the T-cell infiltrates
also were able to show consistent immunologic abnor- seen in oral precancerous lesions were CD8-positive
malities in patients with OSF, which could have impli- and Ia-positive cells and, therefore, presumably were
cations for the malignant transformation of the le- suppressor cells.93
sion.51,79,91.92p rofound alterations of peripheral blood Another interesting link between immune re-
T-lymphocyte subsets were found in OSF, with an im- sponses of patients with OSF and a possible viral origin
balance in the ratios of cells bearing the gamma and mu is also possible. Studies of virally induced diseases also
receptors functionally recognized as cells mediating have shown similar immune derangements as those
suppressor and helper functions, re~pectively.~~ These mentioned earlier, reflected by an abnormality of the
findings subsequently were confirmed further with the CD4/CD8 r a t i ~ . ~We~observed a similar situation in
', ~
use of monoclonal antibodies to T-cell surface determi- cancer of the uterine cervix, a tumor with a possible
n a n t ~Helper T-cells play a vital role in the functional
.~~ viral origin." As discussed earlier, a viral origin also
differentiation of B-cells and the production and elabo- has been suggested for oral precancers, including
ration of interleukin-2. Decreased interleukin-2 produc- 0~~.35-38,42 antigens can elicit changes in mononu-
Viral
tion could result in diminished cellular and humoral clear cell phenotypes with the induction of an inappro-
immune responses. priate specific suppressor T-cell response.99The result-
Investigations of the inflammatory infiltrate into ing immunosuppression would allow spread of the
oral precancers have yielded valuable information. viral antigens and associated transformation of the epi-
Migliorati et ~ 1 showed the infiltrate to be mainly T-
. ~ ~ thelium. This has been reported to occur in HPV infec-
cells, although some B-cells and natural killer (NK) cells t i ~ n , and, with the recent detection of HPV proteins in
~'
were present. Cells expressing Ia-like antigens (immune oral tissues,42this is an important consideration.
response associated antigens) were observed in connec- Of the many immune abnormalities seen in OSF
tive tissue, suggestive of the presence of activated T- and other oral precancers, a most significant one could
cells. A notable feature was the absence of monocytes be related to observations on the role of NK-cells." The
and macrophages. NK-cell can lyse tumor-related and virally infected cells
Specific stimulation and variation of T-lymphocyte without prior sensitization and, hence, have a key role
subtypes in oral precancers could be antigen mediated in the control of tumor cells."' The actual killing of
(viral, tumor, or other antigens) and suggest the occur- target cells by NK-cells is dependent on two steps: tar-
rence of complex cell interactions. Stimulation and acti- get cell binding and subsequent lysis."' Normal pat-
vation of helper T-lymphocytes in dysplastic conditions terns of target binding cells were seen in OSF, but with
can promote antibody synthesis against any tumor-as- reduced active killer cells. This is suggestive of a defect
sociated antigens. Furthermore, the proliferation of cy- in the additional processes that lead to target cell lysis.

2016 CANCER April 25, 2992, Volume 69,No. 8

Treatment of the effector NK-cells with alpha-inter- Autoimmunity and OSF
feron resulted in highly elevated killer cell activity but
no changes in the target binding cell^.^' This could One of the earliest names by which OSF was identified
imply that inactive target binding cells are seen and that was "idiopathic scleroderma of the mouth," and, in
they could be activated or programmed to kill. We in- view of the female preponderance of patients, its pre-
terpreted this to mean that prekiller cells exist that have sentation in middle life, and histologic similarities, the
killer cell receptors and can bind targets but remain in- analogy seems reasonable. The well-documented find-
active until they interact with appropriate stimuli. ings of clinical, immunologic, and histologic abnormali-
These findings open up a whole new rationale for im- ties in OSF and similar reports in other connective tis-
munologic intervention in the therapeutics of oral pre- sue disorders, such as rheumatoid arthritis, progressive
cancers. Biologic response modifiers such as interferon systemic sclerosis, systemic lupus erythematous, and
possibly could modify the pathogenic course of lesions polymyositis, suggest a fundamental autoimmune basis
such as OSF. Another possible candidate would be for the disease. In many autoimmune diseases, genetic
beta-carotene, with low toxicity and powerful immun- factors are thought to be responsible for abnormalities
omodulatory effects, including many on NK-cells. '02-'04 in immunity. Immune response genes may be linked to
Indeed, the use of this vitamin precursor has resulted in the HLA-DR locus of the major histocompatibility com-
clinical remission of some oral precancerous lesions.77 plex in humans, and associations between this locus
Changes in humoral immunity also have been ob- and autoimmune diseases have been ought."^ The DR
served in our studies on OSF and in heavy chewers of antigens are associated with a susceptibility to diseases
betel quid with tobacco. Increased levels of circulating with an autoimmune aspect in their pathogenesis; this
immune complexes (CIC) were noticed in patients with may be because the immune response genes are situ-
OSF and in those who were heavy chewers of betel ated at or near the D locus on chromosome 6. Because
quid compared with nonchewing normal control^.^' A many of the connective disorders, including rheuma-
repeat study of this in our laboratories further con- toid arthritis and systemic lupus erythematous, have
firmed our finding^."^ Similar findings were seen in been reported to be associated with unique HLA-DR
patients with oral cancer and those with oral kerato-
sis,106,107 Historically, CIC and their constituents have I 1
been prominent as factors alleged to be capable of in-
hibiting cell-mediated immune responses in several
types of cancers. 18'o We also have demonstrated pre-
0-'
nutritional
deficiencies
...................
...................
viously the down regulation of NK-cell activity by autol-
ogous serum containing high levels of CIC.83It is possi-
ble for a similar phenomenon to occur in OSF. Cancer
of the oral cavity in India and in many other regions is ...........
.......... 3
associated closely with chewing betel quid and tobacco. J,J,
The carcinogenic potential of the mixture was discussed
earlier. Chewing of the quid causes constant aberration 8 Betal Quid ....... ............3
of the oral mucosa (particularly by the action of slaked
lime, a major component of the quid). This, combined
J.
. r
4 Changes 3-1

with the poor oral hygiene in these people, gives ample
chance for oral infections, enabling the carcinogenic
Abnormalities
+I
components direct access to the cells. The possibility
exists that the carcinogenic action alters the cellular
components in some way, leading to the production of
low-avidity antibodies forming CIC. Preliminary inves-
tigations indicate high levels of immunoglobulin A-
containing CIC.'06~''oa have observed a similar find-
We
...................
...................
ing in other squamous cell cancers,86and at least one
group has described an immunoglobulin A-like serum Oral Submucus Fibrosis
blocking factor in the sera of patients with nasopharyn-
Figure 4. A multifactorial model for the pathogenesis of OSF. Bold
geal carcinoma."' In addition, Basler et al.'l2 have re- arrows show effects mediated by various factors through the
ported persistent elevation of immunoglobulin A-con- immune system, whereas broken arrows show possible direct
taining CIC in head and neck cancers. effects of the factors on oral mucosa.

Pathogenesis of OSF/Pillai et al. 2017

antigen^,"^-"^ a similar association has been sought mation on this disease, which rapidly is becoming an
for OSF. excellent model for studying genetic-environmental-
In an elegant study of 50 unrelated patients of In- immunologic-nutritional interactions in disease patho-
dian origin with OSF, Canniff et ~ 1 . showed increased
"~ genesis.
frequencies of A10, B7, and DR3. It is of interest that in
Indian populations HLA A10, B8, and DR3 occur in
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by Canniff et ~ l . , " ~ A10 and DR3 were increased
that
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~,llOa
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