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 oforal 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, leadingamong 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 toin India, a figure that must have increased sharply. OSFis a condition with a high risk of malignant transforma- extend from the anterior pillars into the soft palate as ation; to date, no conclusive etiologic agent has been iden- delicate reticulum of interlacing white strands that latertified, 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 mucosacinogenic, immunologic, viral, nutritional, and autoim- intermingling with depigmented diseased mucosa. Themune possibilities, all of which also have been impli- floor of the mouth becomes pale and thickened, thecated in the development of oral cancer. This article re- tongue becomes reduced in size and motility, and bandsviews 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 theOral 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 withWith 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 whogressive fibrosis of the lamina propria. The major pre- slowly growing squamous cell carcinomas in one-thirdsenting complaint is a progressive inability to open the of such patients. These observations were confirmedmouth 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 andalong with concomitant muscle degeneration. Patients betel nuts and nutritional deficiencies all have beendescribe 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 bestand 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 CancerCentre, Trivandrurn, India. Genetic Alterations 4 Recipient of the Senior Research Fellowship of the Council forScientific and Industrial Research, India. Address for reprints: Radhakrishna Pillai, PhD, Regional Cancer Cancer researchers have amassed a great deal of dataCentre, 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. 8Figure 1. Histologic changes in OSF showing atrophic epithelium Figure 3. Histologic changes in OSF showing atrophic epitheliumwith loss Of rete Pegs and avascular hYalinized with loss of rete pegs and relatively avascular hyalinized collagenextending downwards from the basement membrane (low-power extending downwards from the basement membrane (high-powerview; 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 flowchange the structure of the genetic material, producing cytometry is used.16point 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 carrytypes of tumors has been noticed to be inherited in genes that can act in a dominant fashion to cause cells tomany situations, such as retinoblastoma, Cowdens undergo malignant transformation. lo Oncogenes or tu-syndrome, Gardners syndrome, and neurofibromato- mor-causing genes often are mutated genes derivedsis.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 havekitts lymphoma, acute and chronic leukemias, and been identified in the human genome, whereas mu-Wilms t ~ m o r . These abnormalities are mostly trans- ~ tated amplified and rearranged oncogenes have beenlocations and deletions with breakpoints at specific lo- found in a wide variety of malignant It iscations. Another chromosomal abnormality that ap- interesting that many of the chromosome deletions andpears 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 biopsyFigure 2. Histologic changes in OSF showing atrophic epitheliumwith loss of rete pegs and relatively avascular hyalinized collagen specimens studied, with 56% showing amplification ofextending downwards from the basement membrane (high-Dower x - 1 at least one of the oncogene^.^ Studies on squamousview of the epithelium; H & E, original magnification X300). cell carcinoma cell lines show considerable chromo-
Pathogenesis of OSFIPillai et al. 201 3some triploidy and tetraploidy. One such study" found laboratory35 and others36 have shown high titers ofaberrations of chromosome 1 in nine head and neck anti-HSV1 antibody in patients with oral cancer andcarcinoma cell lines examined that mainly involved de- precancer, including OSF, compared with patients withletions at lq21, lq32, lq13, or lp22. Two known proto- other cancers and normal controls, but efforts to isolateoncogenes map to these areas. Transfection experi- or characterize virus-specific proteins from lesions werements 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 cluessolid 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 Ofthat 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 aproduce 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 orbers in head and neck carcinomas have been analyzed those at risk of getting it.40 Morphologic virus-likein several studies.26-28 was seen that tumor cells It changes have been seen in verrucous carcinoma^,^ andmostly had an abnormally high DNA content, ranging Loning ef al. recently reported HPV antigens in oralfrom 1.1 to 3.3 times the normal diploid In a No papillomas and leukoplakia~.~ such study has beenunique study of another precancerous lesion of the oral done in OSF, but it could show valuable informationcavity, leukoplakia, Grassel-Pietrusky et ~ 1 . found be- ~ such as the possible role of viruses in oral precancers. Isnign keratoses and mild to moderate leukoplakias to a defect in the immune system necessary for the viralhave 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 developmentof precancers and cancers of the oral cavity. OSF is a Carcinogenspotent oral precancer and may have a strong geneticlink. 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 nutInfectious Agents Associated With Oral Cancer making up the betel quid. In one study, La1 reportedand 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 maturationinent 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 toperimentally, 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 etis not clear whether Candida has a definitive role in the found that patients with oral cancer had higherpathogenesis of OSF or its subsequent malignant trans- aryl hydrocarbon hydroxylase inducibility comparedformation, 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 enzymaticHSV2 with uterine cervix cancer.34 Studies from our nitrosation of nicotine and can be found by reaction of
2014 CANCER April 15, 1992, Volume 69, No. 8salivary nitrates with nornicotine. N-nitrosonornico- atrophy of the mucosa of the upper gastrointestinaltine 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 ofliva is approximately 1000 times that found in cigarette diminished iron stores and the absence of stainablesmoke.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 complexof 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 fromwhether 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 ofquid increased the risk from 4 (without tobacco) to as studies also have reported the development of single ormuch 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 soThis idea is supported by the observation of an elevated evident that Ramanathan66suggested that OSF may beoral cancer incidence related to endemic chewing habits considered the Asian analog of the Plummer-Vinsonin 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 intan 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 studiesaccess 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 anfibroblast proliferation and collagen synthesis in vitro. increased population of susceptible dividing cells andThe flavonoids and tannins from betel nut can stabilize also to a more permeable epithelium. An animalcollagen fibrils and render them resistant to degrada- showed that the development of carcinomas in ratstion 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 overallgether 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 normaland t o b a c ~ o .Yeasts have the capacity to produce ~~,~~ enzymes. Serious impairment of cell-mediated immunecarcinogens, 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 thuspeople. appears that iron can have an important role in the development of oral precancers, including OSF, andNutritional Factors their conversion to cancer. Although most interest has been shown in the roleIron metabolism is important in maintaining the health of iron, other nutritional factors also may be involved inof 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 thatciency may be the most common deficiency state in the of iron, and hence difficult to estimate. Also of greatworld, 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 andscribed the symptom complex of chronic dysphagia and oropharyngeal cancers have subnormal levels of serum
Pathogenesis of OSF/PiJlai et al. 2015vitamin A.74 similar study from Pakistan showed pa- A totoxic rather than suppressor T-cells would contributetients with oral cancer to have significantly lower levels to an antitumor response.94However, criticism of thisof 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 lackbeta-carotene and vitamin A in patients with oral pre- of antigenicity of malignant or potentially malignantcancers 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 effectorImmunologic 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 amongtime, 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 andmunosuppression 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 helperbecoming 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, whereashow this could be directly applicable to progno~is.~ We the latter are Ia negative. Most of the T-cell infiltratesalso were able to show consistent immunologic abnor- seen in oral precancerous lesions were CD8-positivemalities in patients with OSF, which could have impli- and Ia-positive cells and, therefore, presumably werecations for the malignant transformation of the le- suppressor cells.93sion.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 originbalance in the ratios of cells bearing the gamma and mu is also possible. Studies of virally induced diseases alsoreceptors functionally recognized as cells mediating have shown similar immune derangements as thosesuppressor and helper functions, re~pectively.~~ These mentioned earlier, reflected by an abnormality of thefindings 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 possiblen a n t ~Helper T-cells play a vital role in the functional .~~ viral origin." As discussed earlier, a viral origin alsodifferentiation of B-cells and the production and elabo- has been suggested for oral precancers, includingration of interleukin-2. Decreased interleukin-2 produc- 0~~.35-38,42 antigens can elicit changes in mononu- Viraltion 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 theoral 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 OSFtive tissue, suggestive of the presence of activated T- and other oral precancers, a most significant one couldcells. A notable feature was the absence of monocytes be related to observations on the role of NK-cells." Theand 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 defectsociated antigens. Furthermore, the proliferation of cy- in the additional processes that lead to target cell lysis.
2016 CANCER April 25, 2992, Volume 69,No. 8Treatment of the effector NK-cells with alpha-inter- Autoimmunity and OSFferon resulted in highly elevated killer cell activity butno changes in the target binding cell^.^ This could One of the earliest names by which OSF was identifiedimply that inactive target binding cells are seen and that was "idiopathic scleroderma of the mouth," and, inthey 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, thekiller 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, progressivecancers. Biologic response modifiers such as interferon systemic sclerosis, systemic lupus erythematous, andpossibly could modify the pathogenic course of lesions polymyositis, suggest a fundamental autoimmune basissuch as OSF. Another possible candidate would be for the disease. In many autoimmune diseases, geneticbeta-carotene, with low toxicity and powerful immun- factors are thought to be responsible for abnormalitiesomodulatory effects, including many on NK-cells. 02-04 in immunity. Immune response genes may be linked toIndeed, 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 DRserved in our studies on OSF and in heavy chewers of antigens are associated with a susceptibility to diseasesbetel quid with tobacco. Increased levels of circulating with an autoimmune aspect in their pathogenesis; thisimmune 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. Becausequid 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, havefirmed our finding^."^ Similar findings were seen in been reported to be associated with unique HLA-DRpatients with oral cancer and those with oral kerato-sis,106,107 Historically, CIC and their constituents have I 1been prominent as factors alleged to be capable of in-hibiting cell-mediated immune responses in severaltypes of cancers. 18o 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. Cancerof the oral cavity in India and in many other regions is ........... .......... 3associated closely with chewing betel quid and tobacco. J,J,The carcinogenic potential of the mixture was discussedearlier. Chewing of the quid causes constant aberration 8 Betal Quid ....... ............3of the oral mucosa (particularly by the action of slakedlime, a major component of the quid). This, combined J. . r 4 Changes 3-1with the poor oral hygiene in these people, gives amplechance for oral infections, enabling the carcinogenic Abnormalities +Icomponents direct access to the cells. The possibilityexists that the carcinogenic action alters the cellularcomponents in some way, leading to the production oflow-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 onegroup has described an immunoglobulin A-like serum Oral Submucus Fibrosisblocking factor in the sera of patients with nasopharyn- Figure 4. A multifactorial model for the pathogenesis of OSF. Boldgeal carcinoma." In addition, Basler et al.l2 have re- arrows show effects mediated by various factors through theported persistent elevation of immunoglobulin A-con- immune system, whereas broken arrows show possible directtaining 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 anfor 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 inIndian populations HLA A10, B8, and DR3 occur in Referencespositive linkage disequilibrium." The finding reportedby Canniff et ~ l . , " ~ A10 and DR3 were increased that 1. Pindborg JJ, Is submucous fibrosis a precancerous condition insignificantly in a group of patients with OSF, suggests the oral cavity? Int Dent I 1972; 22:474-480.the possibility that a haplotype encoding these antigens 2. Pindborg JJ. Lesions of the oral mucosa to be considered prema-is associated with the susceptibility to OSF. It has been lignant and their epidemiology. In: Mackenzie IC, Dabelsteen E,shown recently that particular haplotypes, rather than Squier CA, eds. Oral Premalignancy. Iowa City: University ofindividual antigens, are associated with susceptibility to Iowa Press, 1980; 2-12. 3. Pindborg JJ, Chawla TN, Srivastava AN, Gupta D, Mehrotrarheumatoid arthritis," insulin-dependent diabetes ML. Clinical aspects of oral submucous fibrosis. Acta Odontolmellitus," and gold-induced nephropathy.20 The de- Scatld 1964; 221679-691.fects in cellular immunity seen in OSF51,79,91*92 are fur- 4. Adwani DG. Histopathological studies before and after Kena-ther suggestive of an autoimmune phenomenon. More- cort in oral submucous fibrosis. MDS Thesis, University of Bom-over, the presence of autoantibodies against gastric bay, India, 1982.cells, smooth muscle, and nuclei also has been docu- 5. Paymaster JC. Cancer of the buccal mucosa: Clinical study of 650 cases in Indian patients. Cancer 1956; 9:431-435.mented.12 Studies on serum from our laboratories also 6 . Kramer IRH. Basic histopathological features of oral premalig-have shown elevated levels of immunoglobulins G and nant lesions. In: Mackenzie IC, Dabelsteen E, Squier CA, eds.~,llOa A similar finding is seen in scleroderma, a disease Oral Premalignancy. Iowa City: University of Iowa Press, 1980;resembling OSF histologically in that epithelial atrophy 15-34.and dermal fibrosis are associated with a chronic inflam- 7. Ames BN, Dunston WE, Yamasaki E, Lee FD. Carcinogens are mutagens: A simple test system combining liver homogenatesmatory infiltrate and an increased frequency of HLA- for activation and bacteria for detection. Proc Nati Arnd Sci U S ADR3 and the haplotypic pair B8/DR3.22823 1973; 70:2281-2286. 8. Mc Cann J, Ames BN. Detection of carcinogens as mutagens inConclusions the salmonella/microsome test: Assay of 300 chemicals: Discus- sion. Proc Nut1 Acad Sci U S A 1976; 73:950-959. 9. Hayward WS, Nee1 BG, Astrin SN. Activation of cellular oncFrom the data currently available on OSF, it appears gene by promoter insertion of ALV induced leukosis. Naturequite clear that the disease is multifactorial, as is the 1981; 290:475-476.case with oral cancer and most of its precursor lesions. It 10. Bishop J N . Cellular oncogenes and retroviruses. A n n Reu Bio-also appears that people in whom OSF develops have a cheni 1983; 52:301-325.genetic predisposition, which could render the oral mu- 11. Cavenee WK, Hansen NF, Nordenskjold Met al. Genetic origins of mutations predisposing to retinoblastoma. Science 1985;cosa more susceptible to chronic inflammatory changes 228~501-502.on exposure to carcinogens. The latter definitely would 12. Swart JGN, Lekkas C, Allard RHB. Oral manifestations in Cow-include betel quid components including tobacco. As dens syndrome. Oral Surg Oral Med Oral Pathol 1985; 59:264-discussed earlier, betel nut extracts can stimulate colla- 268.gen synthesis and fibroblast proliferation.52p53 addi- In 13. Fader M, Kline SN, Spatz SS, Zubrow HJ. Gardeners syndrome (intestinal polyposis, osteomas, sebaceous cysts) and a new den-tion, these extracts also can stabilize the collagen fibrils tal discovery. Oral Surg Oral Med Oral Pathol 1962; 15:153-157.and render them resistant to enzymatic degradation. 14. Hope DG, Mulvihill JJ. Malignancy in neurofibromatosis. AduThe role of genetic abnormalities apart from major his- Neurol 1981; 29:33-43.tocompatibility complex (MHC) variability still needs to 15. Yunis JJ. The chromosomal basis of human neoplasia. Sciencebe defined for OSF. Also related to this is the role of 1983; 221~227-236. 16. Greenbaum E, Koss LG, Elequin F, Silver CE. The diagnosticviruses and their oncogenic potential. It appears that value of flow cytometric DNA measurements in follicular tu-immune dysfunction is a common factor and could be mors of the thyroid gland. Cancer 1985; 56:2011-2015.related to any of the factors discussed so far. Based on 17. Pillai R, Reddiar K, Balaram P. Oncogene expression and oralthese factors, we have suggested a possible model for cancer, I Surg Oncol 1991; 47:102-108.the pathogenesis of OSF, as illustrated in Figure 4. The 18. Pulciani S, Santos E, Lauver AV, Long LK, Barbacid M. Trans- forming genes in human tumors. ] Cell Biochern 1982; 20:51-55.model is indeed speculative and needs to be completed. 19. Willecke K, Schafer R. Human oncogenes. Hun! Genet 1984;Research into genetic, viral, and immunologic aspects is 66:332-139.ongoing in our laboratories. These, along with similar 20. Yokota J, Tsunetsugu-Yokata Y, Battifora H, LeFevre C, Clineapproaches elsewhere, should provide valuable infor- MJ. Alterations of tnyc, myb and rasHaprotooncogenes in cancers
2018 CANCER April 25, 2992, Volume 69, No. 8 are frequent and show clinical correlation. Science 1986; A possible viral pathogenesis. Oral Surg Oral Med Oral Pathol 2311261-263, 1985; 59:52-55.21. Yunis JJ, Soreng AL. Constitutive fragile sites and cancer. Science 42. Loning TH, Reichart P, Staquet MJ, Becker J, Thivolet J. Occur- 1984; 226:1199-1204. rence of papilloma virus structural antigens in oral papillomas22. Cooper GM, Lane MA. Cellular transforming genes and onco- and leukoplakias. Oral Pathol 1984; 13:463-465. genesis. Biochem Biophys Acta 1984; 738:9-25. 43. La1 D. Diffuse oral submucous fibrosis. I All India Dent Assoc23. Krontiris TG, Cooper GM. Transforming activity of human tu- 1953; 26:1-3. mor DNA. Proc Natl Acad Sci U S A 1981; 78: 1181-1184. 44. Valentine JA, Scott J, West CR, St. Hill CA. A histological analy-24. Friedman WH, Rosenblum B, Loewenstein P, Thronton H, Kat- sis of the early effects of alcohol and tobacco usage on human santonis G, Green M. Oncogenes: Preliminary studies in head lingual epithelium. ] Oral Pathol 1985; 14:654-656. and neck cancer. Latyngoscope 1983; 93:1141-1146. 45. Trell E, Bjorlin G, Andreasson L, Korsgaard R, Mattiasson I.25. Friedman WH, Rosenblum B, Loewenstein P, Thronton H, Kat- Carcinoma of the oral cavity in relation to aryl hydrocarbon santonis G, Green M. Oncogenes in laryngeal cancer: Serial pas- hydroxylase inducibility, smoking and dental status. lnt ] Oral sage of transformed cellular DNA. Otolaryngol Head Neck Surg Surg 1981; 10:93-97. 1985; 93~346-350. 46. Hecht SS, Ornaf RM, Hoffmann D. Chemical studies on tobacco26. Roa RA, Carey TE, Passamani PP et al. DNA content of human smoke: Nnitrosonornicotine in tobacco: Analysis of possible con- squamous cell carcinoma lines: Analysis by flow cytometry and tributing factors and biologic implications. ] Natl Cancer Znst chromosome enumeration. Arch Otolaryngol 1985; 111:565- 1974; 54: 1273-1276. 570. 47. Khadim MI. The effect of pan and its ingredients on oral mu-27. Grassel-Pietrusky R, Deinlein E, Hornstein OP. DNA ploidy cosa. IPMA 1977; 27:340-344. rates in oral leukoplakias determined by flow cytometry. 1 Oral 48. Atkinson L, Chester IC, Smyth FG, Ten Seldom REJ. Oral cancer Patho/ 1982; 11~434-436. in New Guinea: A study in demography and aetiology. Cancer28. Hauser-Urfer IH, Stauffer J. Comparative chromosome analysis 1964; 4011289-1292. of nine squamous cell carcinoma lines from tumors of head and 49. Ramanathan K, Ganesan T], Raghavan KV. Carcinoma of the neck. Cytogenet Cell Genet 1985; 39:35-41. tongue in Malaysians. Mod Med Asia 1978; 14:56-59.29. Cawson RA, Lehner T. Chronic hyperplastic candidiasis: Candi- 50. Hirayama T. An epidemiological study of oral and pharyngeal dal leukoplakia. BY Dermatol 1968; 80:9-12. cancer in Central and Southeast Asia. Bull WHO 1966; 34:41-30. Cawson RA. Induction of epithelial hyperplasia by Candida albi- 44. cans. Br ] Dermatol 1973; 89:497-500. 51. Balaram P, Pillai R, Abraham T. Immunology of premalignant31. Russel C, Jones JH. The histology of prolonged candidal infec- and malignant conditions of the oral cavity: 11. Circulating im- tion of the rats tongue. I Oral Pathol 1975; 4:330-332. mune complexes. 1Oral Pathol 1987; 16:389-391.32. Pindborg JJ, Renstrup G, Poulsen HE, Silverman S. Studies in 52. Harvey W, Saitt A, Meghi S, Carniff JP. Stimulation of human oral leukoplakia: V. Clinical and histological signs of malig- buccal fibroblasts in vitro by betel nut alkaloids. Arch Oral Biol nancy. Acta Odontol Scand 1963; 21:407-410. 1986; 31145-49.33. Cawson RA, Binnie WH. Candida, leukoplakia and carcinoma: 53. Kuttan R, Donnely PV, DiFerante N. Collagen treated with (+) A possible relationship. In: Mackenzie IC, Dabeslsteen E, Squier catechin becomes resistant to the action of mammalian collage- CA, eds. Oral Premalignancy. Iowa City: University of Iowa nase. Experentia 1981; 37:221-223. Press, 1980; 59-70. 54. Hirsch JM, Johansson SL, Vahlne A. Effect of snuff and herpes34. Hollinshed AC, Tarro G. Soluble membrane antigens of lip and simplex virus 1 on rat oral mucosa: Possible associations with cervical carcinoma: Reactivity with antibody for herpes virus the development of squamous cell carcinoma. Oral Pafhol non virion antigens. Science 1973; 182713-714. 1984; 13:52-56.35. Kumari TV, Harikumar T, Prabha B, Vivekanandan S, Vasude- 55. Park NH, Sapp JP, Herbosa EG. Oral cancer induced in ham- van DM. Detection of antibodies against herpes simplex virus in sters with herpes simplex infection and simulated snuff dipping. patients with oral cancer. Zndian Cancer 1984; 19:137-140. Oral Surg Oral Med Oral Pathol 1986; 62:164-167.36. Silverman NA, Alexander CJ, Hollinshed AC, Cheretein PB. 56. Krogh P. The role of yeasts in oral cancer by means of endoge- Correlation of tumor burden with in vitro lymphocyte reactivity nous nitrosation. Actu Odontol Scand 1990; 48:85-88. and antibodies to herpes simplex virus in patients with oral 57. Rennie JS, McDonald DG, Dagg JH. Iron and the oral epithe- cancer. Cancer 1970; 37:135-140. lium. R Soc Med 1984; 77:602-604.37. Shillitoe EJ, Hwang CBC, Silverman S, Greenspan JS. Examina- 58. Paterson DR. A clinical type of dysphagia. Laryngol 1919; tion of oral cancer tissue for the presence of the proteins 1 0 4 , 34~289-290. 1CP5, 1 0 6 , 1CP8 and gB of herpes simplex virus type 1. I Natl 59. Kelly AB. Spasm at the entrance of the esophagus. I Larytzgol Cancer Inst 1986; 76:371-376. 1919; 341285-287.38. Brescia RJ, Jenson AB, Lancaster WD, Kurman RJ. The role of 60. Waldenstrom J, Kjellberg SR. The roentgenological diagnosis of human papilloma viruses in the pathogenesis and histologic clas- sideropenic dysphagia. Acta Radiol 1939; 20:618-621. sification of precancerous lesions of the cervix. H u m Pathol 61. Ahlbom HE. Simple achlorhydric anemia, Plummer Vinson 1986; 17:552-556. syndrome and carcinoma of the mouth, pharynx and esophagus39. Greenspan JS, Greenspan D, Lennette ET et al. Replication of in women. Br Med 1936; 2:331-334. Epstein Barr virus within epithelial cells of oral "hairy" leuko- 62. Ahlbom HE. Pradisponierende faktorenfur platten epithelkar- plakia: An AIDS associated lesion. N Engl ] Med 1985; zinom in mund hals and speiserohre. Acta Radiol 1937; 18:163- 313:1564-1565. 167.40. Silverman S, Migliorati CA, Lozada-Nur F, Greenspan D, Con- 63. Wynder EL, Fryer JH. Etiologic considerations of Plummer Vin- ant MA. Oral findings in people with or at high risk for AIDS: A son syndrome. Ann Zntern Med 1958; 259:1106-1109. study of 375 homosexualmales.]Arn DentAssoc 1986; 112:187- 64. Watts JM. The importance of the Plummer Vinson syndrome in 190. the etiology of carcinoma of the upper gastrointestinal tract.41. Eisenberg E, Rosenberg B, Krutchkoff D. Verrucous carcinoma: Postgrad Med I 1961; 37:523-526.
Pathogenesis of OSFIPillai et al. 201965. Shamma MH, Benedict EB. Esophageal webs: A report of 58 cal markers in malignant cervical neoplasia. ] Cancer Res Clin cases and an attempt at classification. N Engl Med 1958; Oncol 1989; 115:583-591. 259:378-380. 87. Pillai R, Balaram P, Bindu 5,Hareendran NK, Padnabhan TK,66. Ramanathan K. Oral submucous fibrosis: An alternative hy- Nair MK. Interleukin 2 production in lymphocyte cultures: A pothesis as to its causes. Med ] Malaysia 1956; 36:243-245. rapid test for cancer associated immunodeficiency in malignant67. Rennie JS, McDonald DG, Dagg JH. Quantitative analysis of the cervical neoplasia. Cancer Lett 1989; 47:205-210. human buccal epithelium in iron deficiency anemia. ] Oral 88. Pillai R, Balaram P, Bindu S, Hareendran NK, Padmanabhan Pathol 1982; 11:39-41. TK, Nair MK. Radiation associated eosinophilia and monocyto-68. Rennie JS, McDonald DG. Quantitative histological analysis of sis in carcinoma of the uterine cervix: A simple reliable prognos- the epithelium of the ventral surface of the hamster tongue in tic indicator. Neoplasma 1990; 37:91-96. iron deficiency. Arch Oral Biol 1982; 27:393-396. 89. Pillai R, Balaram P, Hareendran NK, Bindu 5,Padnabhan TK,69. Prime SS, McDonald DG, Rennie JS. The effect of iron defi- Nair MK. Clinical and prognostic significance of Concanavalin ciency on experimental oral carcinogenesis in the rat. B r ] Cancer A induced suppressor cell activity in malignant cervical neopla- 1983; 471413-416. sia. Br / Obstet Gynecol 1990; 97:357-361.70. Joynson DH, Walker DM, Jacobs A, Dolby AE. Defects of cell 90. Pillai R, Balaram P, Chidambaram S, Padnabhan TK, Nair MK. mediated immunity in patients with iron deficiency anemia. Development of an immunological staging system to prognosti- Lancet 1972; 2:1058-1059. cate cervical neoplasia. Gynecol Oncol 1990; 37:200-205.71. Rennie JS, McDonald DG, Dagg JH. Iron and the oral epithe- 91. Pillai R, Balaram P, Kannan S et al. Clinical implications for oral lium. ] R Soc Med 1984; 77:602-606. precancers of interferon activation of latent natural killer cells72. Jacobs A, Cavil1 I. The oral lesions of iron deficiency anemia: and alteration in kinetics of target cell lysis. Oral Surg Oral Med Pyridoxine and riboflavin status. Br ] Haematol 1968; 14:291- Oral Pathol 1990; 70:458-461. 294. 92. Balaram P, Pillai R, Abraham T. Immunology of premalignant73. Harrison RJ. Vitamin 812 levels in erythrocytes in hypochromic and malignant conditions of the oral cavity. In: Proceedings of anemia. ] Clin Pathol 1971; 24:698-670. the Second UAE Cancer Conference. Abu Dhabi, U.A.E.: Emir-74. Wahi I", Kehar U, Lahiri 8. Factors influencing oral and oropha- ates Medical Association, 1987; 32. ryngeal cancer in India. BY ] Cancer 1965; 19:646-649. 93. Migliorati CA, Migdnorati EKG, Silvermann S, Greenspan D,75. Ibrahim NA, Jafarey NA, Zuberi SJ, Plasma vitamin A and caro- Greenspan JS. Phenotypic identification of mononuclear cells in tene levels in squamous cell carcinoma of the oral cavity and oral premalignant lesions and cancer by monoclonal antibodies. oropharynx. Clin Oncol 1977; 3:303-306. ] Oral Paihol 1986; 15:352-358.76. Stich HF, Homby AP, Mathew B, Sankaranarayanan R, Nair 94. Kimura AK, Wigzell H. Development and function of cytotoxic MK. Response of oral leukoplakias to the administration of vita- T lymphocytes (CTL): In vivo maturation of CTL in the absence min A. Cancer Lett 1988; 40:93-101. of detectable proliferation results as a normal consequence of77. Stich HF, Rosin MP, Hornby AP, Mathew B, Sankaranarayanan alloimmunization. ] Immunol 1983; 130:2056-2059. R, Nair MK. Remission of oral leukoplakias and micronuclei in 95. Robbins DS, Fudenberg HH. Human lymphocyte subpopula- tobacco/betel quid chewers treated with beta carotene and beta tions in metastatic neoplasia: Six years later. N Engl ] Med 1983; carotene plus vitamin A. Int ] Cancer 1988; 42~195-199. 308:1595-1596.78. Urban JL, Schreiber H. Host-tumor interactions in immunosur- 96. Ledbetter JA, Evans RL, Lipinski M, Cunningham-Riddles C, veillance against cancer. Prog Exp Tumor Res 1988; 32:17-68. Good RA, Herzenberg LA. Evolutionary conservation of surface79. Pillai R, Balaram P, Abraham T, Nair MK. Lymphocyte popula- molecules that distinguish T lymphocyte helper-inducer and tions in premalignant and malignant lesions of the oral cavity. suppressor-cytotoxic subpopulations in mouse and man. I Exp Neoplasma 1987; 34:469-479. Med 1981; 153:310-315.80. Pillai R, Balaram P, Padmanabhan TK, Nair MK. Monoclonal 97. Reinherz EL, Hussey RE, Schlossman SF. Absence of expression antibody defined phenotypes of peripheral blood lymphocytes of Ia antigen on human cytotoxic T cells. Immunogenetics 1980; in cancer of the uterine cervix. Am ] Reprod Zmmunol Microbiol 11:421-423. 1987; 14:141-143. 98. Carney WP, Iaacobiello V, Hersch MS. Functional properties of81. Balaram P, Pillai R, Padmanabhan TK, Thomas A, Hareendran T lymphocytes and their subsets in cytomegalovirus mononucle- NK, Nair MK. Immune function in malignant cervical neoplasia. osis. ] Immunol 1983; 130:390-394. Gynecol Oncol 1988; 31:409-423. 99. Biddison WE, Sharrow SO, Shearer GM. T cell subpopulations82. Pillai R, Balaram P, Abraham T, Padmanabhan TK, Nair MK. required for human cytotoxic lymphocyte responses to influ- Natural cytotoxicity and serum blocking in malignant cervical enza virus. ] Immunol 1981; 127:487-491. neoplasia. A m ] Reprod Immunol Microbiol 1988; 16:159-162. 100. Hanna N . The role of natural killer cells in the control of tumor83. Pillai R, Balaram P, Padmanabhan TK, Nair MK. Immunological growth and metastases. Biochem Biophys Acta 1984; 70:213-226. profiles of T lymphocytes in malignant cervical neoplasia. ] Exp 101. Ulberg M, Jondal M. Recycling and target binding capacity of Clin Cancer Res 1988; 7~251-257. human natural killer cells. ] Exp Med 1981; 153~615-621.84. Pillai R, Balaram P, Padmanabhan TK, Abraham P, Nair MK. 102. Rhodes J, Stokes P, Abrams P. Human tumor induced inhibition Interleukin 2 and alpha interferon induced in vitro modulation of interferon action in vitro: Reversal of inhibition by beta caro- of spontaneous cell mediated cytotoxicity in patients with tene. Cancer Zrnmunol Inmunother 1984; 16:189-192. cancer of the uterine cervix undergoing radiotherapy. Acta O n c d 103. Prabhala RH, Maxey V, Hicks MJ, Watson RR. Enhancement of 1989; 28~39-44. the expression of activation markers on human peripheral blood85. Pillai R, Balaram P, Padnabhan TK, Abraham T, Hareendran mononuclear cells by in vitro culture with retinoids and carot- NK, Nair MK. lmmunocompetence in lung cancer: Relation to enoids. / Leukocyte Biol 1989; 45:249-254. extent of tumor burden and histological type. Cancer 1989; 104. Abril ER, Rybski JA, Scuderi P, Watson RR. Beta carotene stimu- 64:1851-1858. lates human leukocytes to secrete a novel cytokine. ] Leukocyte86. Pillai R, Balaram P, Hareendran NK, Bindu S, Padmanabhan Biol 1989; 45~255-259. TK, Nair MK. Immune reactive proteins as prognostic and clini- 105. Remani P, Ankathil R, Vijayan KK, Beevi VMH, Rajendran R,
2020 CANCER April 15, 1992, Volume 69, No. 8 Vijayakumar T. Circulating immune complexes as an immuno- 114. Gibofsky A, Winchester RJ, Patanoyo M. Disease associations of logical marker in premalignant and malignant lesions of the oral the Ia like human alloantigens. ] Exp Med 1978; 148:1728-1732. cavity. Cancer Lett 1988; 40:185-191. 115. Stastny P. Association of the B cell alloantigen DRw4 with rheu-106. Abraham T, Balaram P. Circulating immune complexes in pa- matoid arthritis. N Engl] Med 1978; 298:869-871. tients with squamous cell carcinoma of the oral cavity. ltidiati ] 116. Reinertesin JL, Klippel JH, Johnson AH. B lymphocyte alloanti- Cancer 1987; 24:133-140. gens associated with systemic lupus erythematosus. N Etigl ]107. Scully C. Immunological abnormalities in oral carcinomas and Med 1978; 299:515-518. oral keratosis. 1 Cliti Lab Inrrriuriol 1982; 8:113-116. 117. Canniff JP, Batchelor JR, Dodi IA, Harvey W. HLA typing in oral108. Baldwin RW, Robins RA. Circulating immune complexes in submucous fibrosis. Tissue Antigens 1982; 26:138-142. cancer. In: Sell S , ed. Cancer Markers. Newark, NJ: Humana, 118. Mittal KK, Naik S , Sansonetti N, Cowherd R, Kumar R, Wong 1980; 507-531. DM. The HLA antigens in Indian Hindus. Tissue Antigetis 1982;109. Dahlgren C, Elwing H. Inhibition of polymorphonuclear leuco- 20x223-226. cyte locomotion by antigen-antibody complexes. Inmunology 119. McCluskey 1, Kay I’H, Dawkins RL, Komori K, Christiansen FT, 1980; 49:329-339. McCann UJ. Association of specific MHC supratypes with rheu- matoid arthritis and insulin dependent diabetes mellitus. Disease110. Hellstrom KE, Hellstrom I, Nepon JT. Specific blocking factors: Markers 1983; 1:197-212. Are they important? Biochetn Biophys Acta 1978; 473:121-148. 120. Batchelor JR, Dodi IA, Woo P, Panayi G, Ansell B, Williams PL.110a.Balaram P. Unpublished data, 1991. Family study of gold induced nephritis in patients with rheuma-111. Sundar SK, Abhilashi DV, Kamaraju L et a / . Sera from patients toid arthritis. In: Albert E, Baur M, eds. Histocompatibility Test- with undifferentiated nasopharyngeal carcinoma contain a fac- ing. Berlin: Springer Verlag, 1984; 375-378. tor that abrogates specific Epstein Barr virus antigen induced 121. Canniff JP, Harvey W. The aetiology of oral submucous fibrosis. lymphocyte response. Znt ] Cancer 1982; 29:407-412. Itit Oral Surg 1981; 10:163-167.112. B a s h MW, Maxim PS, Veltri RW. Circulating IgA immune 122. Kallenberg CGM, Van der Voort-Beelen JM, D’Maro J, The TH. complexes in head and neck cancer, nasopharyngeal carcinoma, Scleroderma: Increased frequency of B8/DR3 in scleroderma lung cancer and colon cancer. Fed Proc 1984; 43:1929. and association of the haplotype with impaired cellular immune113. Griffing WL, Moore SB, Luthra HS. Associations of antibodies response. CIin Exp Infrnunol 1981; 43:478-485. to native DNA with HLA DRw3: A major histocompatibility 123. Whiteside TL, Medsger JR, Rodnan GP. HLA DR antigens in complex linked human immune response gene. ] Exp Med 1980; progressive systemic sclerosis (scleroderma). RheurnatoI 1983; 152:319-325. 10:128-131,