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Risk factors and etiopathogenesis of potentially premalignant oral epithelial lesions

Published:March 20, 2018DOI:https://doi.org/10.1016/j.oooo.2018.03.008
      Potentially malignant oral mucosal disease has some ability to give rise to malignancy of the oral epithelium, that is, oral squamous cell carcinoma (OSCC). The present article provides a succinct review of the possible or probable causes of potentially premalignant oral epithelial lesions. There is a focus upon studies that examined the causes or etiologic associations with clinically likely or histopathologically detectable oral epithelial dysplasia.
      Statement of Clinical Relevance
      Oral squamous cell carcinoma affects the quality of life of many individuals across the globe. This malignancy is often preceded by clinically detectable lesions. The present article reviews current knowledge on the risk factors of such potentially malignant diseases.
      Potentially malignant oral mucosal disease has some ability to give rise to malignancy of the oral epithelium, that is, oral squamous cell carcinoma (OSCC). However, as noted in the accompanying articles, there has been and, indeed, remains inconsistency with the terminology or definitions of such disease, hence describing or defining the causes and evolution of such disease is challenging and at times evidence is contradictory and/or misleading. The present article aims to provide a succinct review of the possible or probable causes of disease (in effect, oral epithelial dysplasia [OED]) that have the some potential to give rise to OSCC. Detailed discussion of oral carcinogenesis is out of the scope of this article, although suitable recent reviews can be found elsewhere.
      Oral carcinogenesis is typified by a series of sometimes reversible molecular and cellular events that culminate in neoplasia, and thus it would be expected that some of the known causative factors for potentially malignant oral disease will be similar to those for OSCC. There is substantial evidence that lifestyle factors, including use of tobacco, alcohol, and betel nut (and related products), and probably sexually acquired human papilloma virus (HPV) will cause the vast majority of instances of OSCC, hence it is not surprising that potentially premalignant oral epithelial lesions (PPOELs) may be similarly caused by, or associated with, these factors—other than (at present) infection by HPV. Table I provides a summary of the factors that may drive OED. This article will now consider each of these in more detail.
      Table IRisk factors of oral epithelial dysplasia—and presumably potentially premalignant oral mucosal lesions
      Main known etiological factors
       Tobacco
       Alcohol
       Oral submucous fibrosis
      Potential etiological factors
       Oncogenic HPV types
      Other suggested factors
       Candidal infection
       Treponema pallidum infection
       Oral lichen planus and lichenoid disease (e.g., GvHD)
       Scleroderma
       Genetic disease
        Dyskeratosis congenita
        Bloom disease
        Fanconi anemia
       Others
        Candidal infection
        Hematinic deficiency
        Others
      GvHD, graft-versus-host disease; HPV, human papilloma virus.

      Likely Common Risk Factors of Potentially Malignant Oral Mucosal Disease

      Tobacco products

      An association between tobacco use and oral cancer has long been established. Several systematic reviews have strongly supported the association between distinctive forms of tobacco exposure (both smoked and smokeless) with an increased risk of OSCC.
      • Awan K.H.
      • Patil S.
      Association of smokeless tobacco with oral cancer - evidence from the south asian studies: a systematic review.
      • Sinha D.N.
      • Abdulkader R.S.
      • Gupta P.C.
      Smokeless tobacco-associated cancers: a systematic review and meta-analysis of Indian studies.
      • Munshi T.
      • Heckman C.J.
      • Darlow S.
      Association between tobacco waterpipe smoking and head and neck conditions: a systematic review.
      • Chang C.M.
      • Corey C.G.
      • Rostron B.L.
      • Apelberg B.J.
      Systematic review of cigar smoking and all cause and smoking related mortality.
      • Gupta B.
      • Johnson N.W.
      Systematic review and meta-analysis of association of smokeless tobacco and of betel quid without tobacco with incidence of oral cancer in South Asia and the Pacific.
      • Khan Z.
      • Tonnies J.
      • Muller S.
      Smokeless tobacco and oral cancer in South Asia: a systematic review with meta-analysis.
      • Petti S.
      • Masood M.
      • Scully C.
      The magnitude of tobacco smoking-betel quid chewing-alcohol drinking interaction effect on oral cancer in South-East Asia. A meta-analysis of observational studies.
      • Weitkunat R.
      • Sanders E.
      • Lee P.N.
      Meta-analysis of the relation between European and American smokeless tobacco and oral cancer.
      • Gandini S.
      • Botteri E.
      • Iodice S.
      • et al.
      Tobacco smoking and cancer: a meta-analysis.
      • Sadri G.
      • Mahjub H.
      Tobacco smoking and oral cancer: a meta-analysis.
      Although oral leukoplakia is the most common PPOEL, its association with tobacco use has not been evaluated as well as that of OSCC. In addition, changes in the definitions and nomenclature of PPOELs have caused interpretation of results of previous studies to be challenging.
      • Arduino P.G.
      • Bagan J.
      • El-Naggar A.K.
      • Carrozzo M.
      Urban legends series: oral leukoplakia.
      Although the association between tobacco consumption and oral leukoplakia has long been described,
      • Silverman Jr, S.
      • Gorsky M.
      • Lozada F.
      Oral leukoplakia and malignant transformation. A follow-up study of 257 patients.
      • Pindborg J.J.
      • Roed-Peterson B.
      • Renstrup G.
      Role of smoking in floor of the mouth leukoplakias.
      • Baric J.M.
      • Alman J.E.
      • Feldman R.S.
      • Chauncey H.H.
      Influence of cigarette, pipe, and cigar smoking, removable partial dentures, and age on oral leukoplakia.
      a genuine evidence-based causal link is still missing.
      • Arduino P.G.
      • Bagan J.
      • El-Naggar A.K.
      • Carrozzo M.
      Urban legends series: oral leukoplakia.
      Nevertheless, non-prospective observational studies have pointed to an association between smoking and oral leukoplakia.
      • Dietrich T.
      • Reichart P.A.
      • Scheifele C.
      Clinical risk factors of oral leukoplakia in a representative sample of the US population.
      Similarly, simple logic would suggest that a disease process that ultimately causes oral cancer will have similar etiological factors as OSCC. A large population-based Taiwanese study showed that high-risk individuals, namely, cigarette smokers and betel nut chewers, present a 2.7 relative risk of developing oral leukoplakia or oral cancer and that screening them seems to be an effective approach to reduce oral cancer–related mortality.
      • Chuang S.L.
      • Su W.W.
      • Chen S.L.
      • et al.
      Population-based screening program for reducing oral cancer mortality in 2,334,299 Taiwanese cigarette smokers and/or betel quid chewers.
      In fact, Taiwanese individuals with oral cancer seems to smoke 469 packs of cigarettes per year, for 28.5 years, together with 12,508 betel quid pieces per year, for 23.3 years, before presenting with oral cancer.
      • Tsai K.Y.
      • Su C.C.
      • Lin Y.Y.
      • Chung J.A.
      • Lian I.
      Quantification of betel quid chewing and cigarette smoking in oral cancer patients.
      A retrospective study of 15,811 US individuals demonstrated that risk factors for oral leukoplakia included male gender, current cigarette or pipe/cigar use, smokeless-tobacco use, ever alcohol consumption, and diabetes mellitus. The number of cigarettes smoked per day was closely associated with a risk of oral leukoplakia. A Hungarian cross-sectional study performed during an oral screening program found that 3.7% of the individuals presented with PPOELs and that among these, 88% reported tobacco use.
      • Dombi C.
      • Vörös-Balog T.
      • Czeglédy A.
      • Hermann P.
      • Vincze N.
      • Bánóczy J.
      Risk group assessment of oral precancer attached to X-ray lung-screening examinations.
      In individuals residing in rural United States, smokeless tobacco was strongly associated with the presence of oral leukoplakia.
      • Fisher M.A.
      • Bouquot J.E.
      • Shelton B.J.
      Assessment of risk factors for oral leukoplakia in West Virginia.
      Individuals with tobacco-related lesions have an increased risk of OED.
      • Samatha Y.
      • Sankar A.J.
      • Ganapathy K.S.
      • Srinivas K.
      • Ankineedu D.
      • Choudary A.L.
      Clinicopathologic evaluation of lesions associated with tobacco usage.
      Tobacco positively influences the risk of PPOELs (particularly leukoplakia) and the presence of mucosal lesions, which, predictably, include nicotinic stomatitis.
      • Al-Attas S.A.
      • Ibrahim S.S.
      • Amer H.A.
      • Darwish Z.-S.
      • Hassan M.H.
      Prevalence of potentially malignant oral mucosal lesions among tobacco users in Jeddah, Saudi Arabia.
      • Chandra P.
      • Govindraju P.
      Prevalence of oral mucosal lesions among tobacco users.
      Yet this latter disorder does not commonly transform to malignancy. A recent meta-analysis has indicated that the malignant transformation of PPOELs is influenced by the clinical appearance (e.g., nonhomogeneous leukoplakia is more likely to transform compared with homogeneous leukoplakia) and location (the lateral border of the tongue is a site of particular concern).
      • Narayan T.V.
      • Shilpashree S.
      Meta-analysis on clinicopathologic risk factors of leukoplakias undergoing malignant transformation.
      In addition, smoking cessation seems to produce beneficial results to populations by reducing the prevalence of oral leukoplakia and the incidence of oral cancer, thus leading to a time-dependent benefit to former smokers.
      • Warnakulasuriya S.
      • Dietrich T.
      • Bornstein M.M.
      • et al.
      Oral health risks of tobacco use and effects of cessation.
      More importantly, smoking cessation in or before middle age helps avoid most of the eventual risk of developing cancer of the oral cavity; 10 years after smoking cessation, the risk of oral cancer seems to be similar to that of a never-smoker.
      • Warnakulasuriya S.
      • Dietrich T.
      • Bornstein M.M.
      • et al.
      Oral health risks of tobacco use and effects of cessation.
      • Bosetti C.
      • Gallus S.
      • Peto R.
      • et al.
      Tobacco smoking, smoking cessation, and cumulative risk of upper aerodigestive tract cancers.
      This approach also may reverse the presence of oral leukoplakias
      • Roed-Petersen B.
      Effect on oral leukoplakia of reducing or ceasing tobacco smoking.
      and even reduce the prevalence of PPOELs.
      • Gupta P.C.
      • Murti P.R.
      • Bhonsle R.B.
      • Mehta F.S.
      • Pindborg J.J.
      Effect of cessation of tobacco use on the incidence of oral mucosal lesions in a 10-yr follow-up study of 12,212 users.
      The literature contains numerous reports on the etiologic mechanisms by which smokeless tobacco can cause cellular changes that may result in PPOELs; however, these will not be reviewed in detail here. Smokeless tobacco products contain several carcinogens, with nitrosamines being the most significant, and these products can be consumed through chewing and snuff use.
      • Warnakulasuriya K.A.
      • Ralhan R.
      Clinical, pathological, cellular and molecular lesions caused by oral smokeless tobacco—a review.
      Among them, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N0-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are the most prevalent tobacco-specific nitrosamines (TSNAs) with high carcinogenic potency linked to several tumors.
      • Nilsson R.
      The molecular basis for induction of human cancers by tobacco specific nitrosamines.
      • Perez-Ortuno R.
      • Martínez-Sánchez J.M.
      • Fu M.
      • et al.
      Assessment of tobacco specific nitrosamines (TSNAs) in oral fluid as biomarkers of cancer risk: a population-based study.
      NNN was demonstrated to be abundant in the oral fluids of smokers as well as nonsmokers and associated with esophageal and oral cancers, given that the NNN/cotinine ratio is increased in secondhand smoke.
      • Perez-Ortuno R.
      • Martínez-Sánchez J.M.
      • Fu M.
      • et al.
      Assessment of tobacco specific nitrosamines (TSNAs) in oral fluid as biomarkers of cancer risk: a population-based study.
      The use of smokeless tobacco products has increased considerably across the globe, probably as a consequence of escalation in the cost of cigarettes and the incorrect belief that smokeless tobacco is less harmful to the mouth compared with smoked tobacco. Although smokeless tobacco has long been associated with oral cancer risk, there is still a misconception of its “harmless nature” associated with the reduced tobacco-related disease risks.
      • Mallery S.R.
      • Tong M.
      • Michaels G.C.
      • Kiyani A.R.
      • Hecht S.S.
      Clinical and biochemical studies support smokeless tobacco's carcinogenic potential in the human oral cavity.
      Nevertheless, significant variation in its composition, with varying amount of several carcinogens, associated with long-term TSNAs exposure limits the interpretation of epidemiology studies.
      • Boffetta P.
      • Hecht S.
      • Gray N.
      • Gupta P.
      • Straif K.
      Smokeless tobacco and cancer.
      Certainly, oral leukoplakia can precede OSCC in snuff users,
      • Warnakulasuriya K.A.
      • Ralhan R.
      Clinical, pathological, cellular and molecular lesions caused by oral smokeless tobacco—a review.
      and a recent meta-analysis of studies derived from Southern Asia demonstrated that smokeless tobacco is a risk for all PPOELs (odds ratio [OR] = 20.0; 95% confidence interval [CI] 12.3-32.5), although the risk for oral leukoplakia is not as substantial (OR = 4.33; 95% CI 1.4-13.2).
      • Khan Z.
      • Khan S.
      • Christianson L.
      • Rehman S.
      • Ekwunife O.
      • Samkange-Zeeb F.
      Smokeless tobacco and oral potentially malignant disorders in south asia: a systematic review and meta-analysis.
      Shammah, a traditional form of snuff dipping tobacco, is a significant risk factor of oral leukoplakia, particularly in Yemenis; current Shammah use is significantly associated with the presence of PPOELs (OR = 12.99; 95% CI 6.34-26.59). A study of US professional baseball players demonstrated that a reduction in the frequency of oral leukoplakia may be linked to a fall in consumption of smokeless tobacco over a 10-year period.
      • Sinusas K.
      • Coroso J.G.
      A 10-yr study of smokeless tobacco use in a professional baseball organization.
      Besides PPOELs, smokeless tobacco may impact overall oral health, increasing the rates of tooth loss, edentulousness, and gingival recession.
      • Agbor M.A.
      • Azodo C.C.
      • Tefouet T.S.
      Smokeless tobacco use, tooth loss and oral health issues among adults in Cameroon.
      Unsurprisingly, clinically detectable oral mucosal changes are common in tobacco chewers—for example, arising in nearly half from a sample of adults from low-income groups in India.
      • Reddy S.S.
      • Prashanth R.
      • Yashodha Devi B.K.
      • Chugh N.
      • Kaur A.
      • Thomas N.
      Prevalence of oral mucosal lesions among chewing tobacco users: a cross-sectional study.
      Some lesions, such as oral lichen planus, are unlikely, however, despite being potentially malignant, to be caused by smokeless (or indeed smoked) tobacco. A cohort study reported that a 6-week cessation of smokeless tobacco habit in young males caused resolution of almost all instances of leukoplakia.
      • Martin G.C.
      • Brown J.P.
      • Eifler C.W.
      • Houston G.D.
      Oral leukoplakia status six weeks after cessation of smokeless tobacco use.
      This does, however, seem a rather remarkable finding that warrants further investigation. Cessation of tobacco use is clearly beneficial to many aspects of oral health, although there is a need for further supportive studies.
      • Lodi G.
      • Franchini R.
      • Warnakulasuriya S.
      • et al.
      Interventions for treating oral leukoplakia to prevent oral cancer.

      Alcohol products

      Alcohol is a risk factor for many cancers, including those of the head and neck. The type of alcoholic beverage and the frequency of consumption can influence any cancer risk, and the risk is increased with concomitant tobacco use.
      IARC Working Group on the Evaluation of Carcinogenic Risks to Humans
      Alcohol consumption and ethyl carbamate.
      • Talamini R.
      • Franceschi S.
      • Barra S.
      • La Vecchia C.
      The role of alcohol in oral and pharyngeal cancer in non-smokers, and of tobacco in non-drinkers.
      Oral cancer risk seems to be related to overall alcohol consumption (drink-years) and not to number of drinks per day.
      • Lubin J.H.
      • Purdue M.
      • Kelsey K.
      • et al.
      Total exposure and exposure rate effects for alcohol and smoking and risk of head and neck cancer: a pooled analysis of case-control studies.
      Although there is a strong positive association between alcohol and OSCC risk, the evidence of such an interaction between alcohol and PPOELs is less strong or less evident.
      Protein adducts with aldehydic end products are expressed in oral leukoplakia and OSCC,
      • Warnakulasuriya S.
      • Parkkila S.
      • Nagao T.
      • et al.
      Demonstration of ethanol-induced protein adducts in oral leukoplakia (pre-cancer) and cancer.
      and an association between alcohol consumption and oral leukoplakia was found in a large cross-sectional study. A case-control study in India found that alcohol drinking was a significant risk factor for oral leukoplakia—even among non-users of tobacco or other related products—this being particularly so in females.
      • Hashibe M.
      • Sankaranarayanan R.
      • Thomas G.
      • et al.
      Alcohol drinking, body mass index and the risk of oral leukoplakia in an Indian population.
      A previous cross-sectional study reported that 7 + alcoholic drinks per week was associated with OED (OR = 2.4) after controlling for confounders, such as tobacco use.
      • Morse D.E.
      • Katz R.V.
      • Pendrys D.G.
      • et al.
      Smoking and drinking in relation to oral epithelial dysplasia.
      In 2007, the same group interviewed patients with OED and OSCC and observed that smoking was similarly associated with both conditions, but drinking was more strongly associated with oral cancer.
      • Morse D.E.
      • Psoter W.J.
      • Cleveland D.
      • et al.
      Smoking and drinking in relation to oral cancer and oral epithelial dysplasia.
      A large prospective cohort study reported that alcohol use was an independent risk factor for PPOELs; alcohol drinkers had a higher risk compared with non-drinkers for both PPOELs and oral dysplasia, and the association with tobacco had a more-than-additive (i.e., not synergistic) effect on PPOEL risk.
      • Maserejian N.N.
      • Joshipura K.J.
      • Rosner B.A.
      • Giovannucci E.
      • Zavras A.I.
      Prospective study of alcohol consumption and risk of oral premalignant lesions in men.
      At the present time, although appropriately designed long-term prospective studies will need to confirm this, alcohol should be considered an etiologic risk factor for PPOEL.

      Oral submucous fibrosis

      Oral submucous fibrosis (OSMF) is caused by exposure to a host of agents, particularly arecoline in areca nut. Present evidence suggests a 3.72% or greater malignant transformation rate for OSF,
      • Ekanayaka R.P.
      • Tilakaratne W.M.
      Oral submucous fibrosis: review on mechanisms of malignant transformation.
      • Yang P.Y.
      • Chen Y.T.
      • Wang Y.H.
      • et al.
      Malignant transformation of oral submucous fibrosis in Taiwan: a nationwide population-based retrospective cohort study.
      with the rate of occurrence of leukoplakia within OSMF being about 24% and being a predictor of later OSCC. The mechanisms, including genetic and epigenetic events that culminate in OSCC, that underlie the malignant potential of OMSF have been well reviewed elsewhere.
      • Ekanayaka R.P.
      • Tilakaratne W.M.
      Oral submucous fibrosis: review on mechanisms of malignant transformation.
      An oncogenic human papilloma virus (HPV) subtype—that is, potential risk factor human papilloma virus (HPV)—is now recognized as a cause of OSCC. It would, thus, be expected that such an association also exists with respect to PPOELs. The oncogenic types, particularly HPV-16 and HPV-18, are, like the cervical, penile, and perianal mucosae, the most likely causes of oral mucosal carcinogenesis.
      • Ghittoni R.
      • Accardi R.
      • Chiocca S.
      • Tommasino M.
      Role of human papillomaviruses in carcinogenesis.
      Oral acquisition of HPV is positively associated with sexual behavior.
      • D'Souza G.
      • McNeel T.S.
      • Fakhry C.
      Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer.
      • Sathish N.
      • Wang X.
      • Yuan Y.
      Human Papillomavirus (HPV)-associated oral cancers and treatment strategies.
      Nevertheless, the association with OSCC only really applies to disease of the posterior tongue, tonsils, and upper pharynx.
      • Chen X.
      • Zhao Y.
      Human papillomavirus infection in oral potentially malignant disorders and cancer.
      • Hubbers C.U.
      • Akgul B.
      HPV and cancer of the oral cavity.
      Prevalence of HPV DNA and p16 prevalence in OSCC (in general) can be higher here than in the normal oral epithelium, but it seems to be lower than in oropharyngeal carcinomas.
      • Syrjanen S.
      • Lodi G.
      • von Bültzingslöwen I.
      • et al.
      Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review.
      • Lingen M.W.
      • Xiao W.
      • Schmitt A.
      • et al.
      Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas.
      The use of different techniques for viral detection, lack of data on sites of origin of samples, and unclear information on exposures to risk factors limits current understanding of the role of HPV in OSCC, but evidence does support the belief that HPV is a risk factor for some, but not all, OSCCs.
      • Syrjanen S.
      • Lodi G.
      • von Bültzingslöwen I.
      • et al.
      Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review.
      • Lingen M.W.
      • Xiao W.
      • Schmitt A.
      • et al.
      Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas.
      • Kruger M.
      • Pabst A.M.
      • Walter C.
      • et al.
      The prevalence of human papilloma virus (HPV) infections in oral squamous cell carcinomas: a retrospective analysis of 88 patients and literature overview.
      It might, thus, be expected that there is a demonstrable association between oncogenic types of HPV and PPOELs,
      • Chen X.
      • Zhao Y.
      Human papillomavirus infection in oral potentially malignant disorders and cancer.
      • Marini A.
      • Wagenmann M.
      • Ting E.
      • Hengge U.R.
      Squamous cell cancer and human papillomavirus infection in oral lichen planus: case report and literature review.
      but available data are presently not perhaps as consistent as those for some OSCCs. The detection rate of HPV in oral leukoplakia varies greatly according to the methods of analysis.
      • Campisi G.
      • Giovannelli L.
      • Aricò P.
      • et al.
      HPV DNA in clinically different variants of oral leukoplakia and lichen planus.
      Rates of HPV DNA detection have been 17.6% in oral leukoplakia and 19.7% in oral lichen planus (OLP)—much higher rates than those for healthy oral mucosa (5.6%).
      • Ostwald C.
      • Rutsatz K.
      • Schweder J.
      • Schmidt W.
      • Gundlach K.
      • Barten M.
      Human papillomavirus 6/11, 16 and 18 in oral carcinomas and benign oral lesions.
      Others have reported similar results for HPV DNA in both oral leukoplakia (22.2%) and OLP (15.4%), with oncogenic types (16 and 18) being the most commonly identified subtypes.
      • Ostwald C.
      • Rutsatz K.
      • Schweder J.
      • Schmidt W.
      • Gundlach K.
      • Barten M.
      Human papillomavirus 6/11, 16 and 18 in oral carcinomas and benign oral lesions.
      Sikka et al.
      • Sikka S.
      • Sikka P.
      Association of human papilloma virus 16 infection and p53 polymorphism among tobacco using oral leukoplakia patients: a clinicopathologic and genotypic study.
      found HPV DNA in more than 40% of oral leukoplakia lesions, but its presence was not associated with any particular grade of dysplasia. p16 immunoexpression has similarly yielded variations in HPV presence in PPOELs.
      • Prakash P.
      • Khandare M.
      • Kumar M.
      • et al.
      Immunohistochemical detection of p16(INK4 a) in leukoplakia and oral squamous cell carcinoma.
      It might have been expected that a strong link between HPV and PPEOLs would be reflected in a higher rate of HPV (particularly oncogenic types) in erythroplakia than in leukoplakia, but HPV infection rates in the former (although not evaluated to any notable extent) seem to be of similar rates as those of the latter.
      • Baig S.
      • Lucky M.H.
      • Qamar A.
      • et al.
      Human papilloma virus and oral lesions in gutka eating subjects in Karachi.
      An early meta-analysis of case reports and case series showed that HPV is 3 times more likely to be detected in PPOELs and 4.7 times more likely to be identified in OSCC than in the normal mucosa.
      • Miller C.S.
      • Johnstone B.M.
      Human papillomavirus as a risk factor for oral squamous cell carcinoma: a meta-analysis, 1982-1997.
      A more recent meta-analysis reported that HPV oncogenic types have a higher prevalence in PPOELs than in the healthy epithelium; this association applied to both cellular or tissue samples and thus supports the notion of a strong association between HPV and PPOELs.
      • Syrjanen S.
      • Lodi G.
      • von Bültzingslöwen I.
      • et al.
      Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review.
      Nevertheless, prospective studies are necessary to evaluate whether the presence of HPV may predict malignant progression of PPOELs.
      • Syrjanen S.
      • Lodi G.
      • von Bültzingslöwen I.
      • et al.
      Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review.
      • Yang S.W.
      • Lee Y.S.
      • Chen T.A.
      • Wu C.J.
      • Tsai C.N.
      Human papillomavirus in oral leukoplakia is no prognostic indicator of malignant transformation.
      Furthermore, there are concerns that any association between the oncogenic types of HPV and oral leukoplakia (or OED) may not have considered the site of leukoplakia (which is bound to be of relevance)
      • Lerman M.A.
      • Almazrooa S.
      • Lindeman N.
      • Hall D.
      • Villa A.
      • Woo S.B.
      HPV-16 in a distinct subset of oral epithelial dysplasia.
      and the social background of affected individuals. It may be probable, based on the patterns of HPV-associated OSCC, that virally driven PPOEL is a distinct group
      • Lerman M.A.
      • Almazrooa S.
      • Lindeman N.
      • Hall D.
      • Villa A.
      • Woo S.B.
      HPV-16 in a distinct subset of oral epithelial dysplasia.
      in which affected individuals may have been exposed to alcohol, tobacco, and HPV types that are different from those in patients of the past, and hence they may have disease that is driven more by HPV than by tobacco and/or alcohol and that affects the posterior aspects of the tongue and mouth.
      Oncogenic and non-oncogenic types of HPV have been detected in OLP, and, indeed, a systemic review has suggested an association between HPV and OLP.
      • Syrjanen S.
      • Lodi G.
      • von Bültzingslöwen I.
      • et al.
      Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review.
      There is insufficient evidence to state that either HPV acquisition or carriage is associated with particular clinical or histopathologic types of OLP or that the presence of oncogenic types of HPV influence any malignant potential of OLP. Finally, there is no consistent pattern of carriage of particular HPV types (oncogenic or non-oncogenic) across the globe. Thus, at the present time, although oncogenic types of HPV can exist within the mouths or lesions of patients with OLP, it remains unclear if such an association is of relevance to the etiopathogenesis and malignant potential of OLP. HPV, including the oncogenic types, has been detected in oral submucous fibrosis. There are, however, few relevant studies,
      • Chen X.
      • Zhao Y.
      Human papillomavirus infection in oral potentially malignant disorders and cancer.
      and thus, at the present time, it cannot be concluded that HPV is a cause of the premalignant potential of oral submucous fibrosis.

      Uncommon Risk Factors

      Candidal infection

      It has long been proposed that candidal infection may be a cause of OED, although there remains no definitive supportive evidence. Since the 1980s, it has been suggested that the production of nitrosamines by the Candida species may influence the malignant transformation of PPOELs and oral cancer risk.
      • Krogh P.
      • Hald B.
      • Holmstrup P.
      Possible mycological etiology of oral mucosal cancer: catalytic potential of infecting Candida albicans and other yeasts in production of N-nitrosobenzylmethylamine.
      However, although the presence of Candida may be associated with PPOELs and OSCC risk,
      • McCullough M.
      • Jaber M.
      • Barrett A.W.
      • Bain L.
      • Speight P.M.
      • Porter S.R.
      Oral yeast carriage correlates with presence of oral epithelial dysplasia.
      truly convincing data that this fungal infection drives oral carcinogenesis are remarkably lacking. A retrospective study reported candidal infection to be associated with dysplasia and tongue lesions and suggested that antifungal treatment should be considered in these cases,
      • Wu L.
      • Feng J.
      • Shi L.
      • Shen X.
      • Liu W.
      • Zhou Z.
      Candidal infection in oral leukoplakia: a clinicopathologic study of 396 patients from eastern China.
      but there is no convincing evidence that this has any long-term clinical benefit; this may be a medico-legal issue. A cross-sectional study observed that nearly half the oral leukoplakias cases were infected with Candida spp., mostly Candida albicans, with tobacco smoking, betel-quid chewing, and alcohol consumption being strongly associated with the presence of candidal infection.
      • Dilhari A.
      • Weerasekera M.M.
      • Siriwardhana A.
      • et al.
      Candida infection in oral leukoplakia: an unperceived public health problem.
      Betel-quid chewing was also associated with Candida infection in a study on Cambodian females.
      • Reichart P.A.
      • Schmidtberg W.
      • Samaranayake L.P.
      • Scheifele C.
      Betel quid-associated oral lesions and oral Candida species in a female Cambodian cohort.
      Patients with OSMF can have an elevated level of candidal infection, and the number of colony forming units may increase with longer duration of the betel-quid chewing habit.
      • Kamat M.S.
      • Vanaki S.S.
      • Puranik R.S.
      • Puranik S.R.
      • Kaur R.
      Oral Candida carriage, quantification, and species characterization in oral submucous fibrosis patients and healthy individuals.
      Patients with OLP also have higher rates of candidal infection compared with healthy individuals, with a shift toward a species other than C. albicans.
      • Kragelund C.
      • Kieffer-Kristensen L.
      • Reibel J.
      • Bennett E.P.
      Oral candidosis in lichen planus: the diagnostic approach is of major therapeutic importance.
      Patients with chronic mucocutaneous candidiasis, particularly those with autoimmune polyendocrinopathy candidal ectodermal dystrophy may be at risk of OSCC and esophageal malignancy.
      • Shephard M.K.
      • Schifter M.
      • Palme C.E.
      Multiple oral squamous cell carcinomas associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
      • Delsing C.E.
      • Bleeker-Rovers C.P.
      • van de Veerdonk F.L.
      • et al.
      Association of esophageal candidiasis and squamous cell carcinoma.
      This may reflect the generation of carcinogenic agents by specific Candida strains or perhaps altered immune surveillance, but it is independent of tobacco and/or alcohol exposure. Thus, in highly rare instances, it may be possible for Candida species to cause OED or neoplasia. Nevertheless, despite evidence that candidal carriage may be more frequent or of higher load in patients with PPOELs compared with others, that some candidal species can generate carcinogenic agents, and that candidal infection can be associated with OED or OSCC, there is no substantial or consistent proof that this infection is a common cause or driver of the evolution and malignant transformation of PPOEL.

      Treponema pallidum infection

      Syphilis, which is caused by Treponema pallidum, has long been proposed as a risk factor of OSCC; however, data to support this notion are limited, and there are very few reports of the precise histopathology of “syphilitic leukoplakia” confirming that this is a truly potentially malignant lesion. An epidemiologic study of 16,420 people diagnosed with syphilis and resident in the United States (1972-1987) did, however, find an elevated standardized incidence ratio for cancers of the oral cavity—particularly the tongue. However, it remains unclear whether any risk of OSCC (and PPOELs) in syphilis is a direct consequence of infection or its treatment or the result of recognized causative factors for oral malignancy.
      • Leao J.C.
      • Gueiros L.A.
      • Porter S.R.
      Oral manifestations of syphilis.

      Oral lichen planus

      OLP is considered a potentially malignant disorder, although lack of clear diagnostic criteria and conflicting reports on malignant transformation have hampered understanding of the precise likelihood of OLP transforming to OSCC.
      • Cheng Y.S.
      • Gould A.
      • Kurago Z.
      • Fantasia J.
      • Muller S.
      Diagnosis of oral lichen planus: a position paper of the American Academy of Oral and Maxillofacial Pathology.
      • van der Meij E.H.
      • Schepman K.P.
      • van der Waal I.
      The possible premalignant character of oral lichen planus and oral lichenoid lesions: a prospective study.
      • van der Meij E.H.
      • Mast H.
      • van der Waal I.
      The possible premalignant character of oral lichen planus and oral lichenoid lesions: a prospective five-year follow-up study of 192 patients.
      Only a small subset of OLP lesions would seem to transform to malignancy, but the OSCCs may be multiple and may not always be at sites of existing OLP.
      • Mignogna M.D.
      • Fedele S.
      • Lo Russo L.
      • Mignogna C.
      • de Rosa G.
      • Porter S.R.
      Field cancerization in oral lichen planus.
      A systematic review of 16 observational studies of 7086 patients with OLP suggested an average rate of 1.09% for malignant transformation, with an annual transformation rate ranging from 0.36% to 0.69%. The tongue was the most common location in which malignant transformation occurred.
      • Fitzpatrick S.G.
      • Hirsch S.A.
      • Gordon S.C.
      The malignant transformation of oral lichen planus and oral lichenoid lesions: a systematic review.
      A later meta-analysis of 57 studies that included 19,676 patients reported a malignant transformation rate of 1.1% with tobacco smoking, alcohol use, and HPV infection being possible risk factors for malignant transformation.
      • Aghbari S.M.H.
      • Abushouk A.I.
      • Attia A.
      • et al.
      Malignant transformation of oral lichen planus and oral lichenoid lesions: a meta-analysis of 20095 patient data.
      The exact mechanism by which OLP induces OSCC is not known, and, indeed, there would seem to be few, if any, studies that demonstrate that OLP transforms to OSCC via histopathologically or clinically proven PPOELs. Certainly, there are molecular parallels with other chronic inflammatory disorders (that are known to cause malignancy—e.g., ulcerative colitis, Barrett esophagitis, and others).
      • Georgakopoulou E.A.
      • Achtari M.D.
      • Achtaris M.
      • Foukas P.G.
      • Kotsinas A.
      Oral lichen planus as a preneoplastic inflammatory model.
      • Grivennikov S.I.
      • Greten F.R.
      • Karin M.
      Immunity, inflammation, and cancer.
      Image-based DNA ploidy (i.e., indicating gross DNA changes) can be abnormal in some OLP lesions and may predict later malignant transformation of some, but not all, lesions. Aldehyde dehydrogenase status may increase the risk of OSCC (adjusted OR 6.71) in patients with OLP.
      • Xu Z.
      • Shen Z.
      • Shi L.
      • Sun H.
      • Liu W.
      • Zhou Z.
      Aldehyde dehydrogenase 1 expression correlated with malignant potential of oral lichen planus.
      Moreover, expression of Bmi1, a stem cell marker, may be associated with an elevated risk of malignant transformation of OLP.
      • Ma L.
      • Wang H.
      • Yao H.
      • Zhu L.
      • Liu W.
      • Zhou Z.
      Bmi1 expression in oral lichen planus and the risk of progression to oral squamous cell carcinoma.
      Thus, at the present time, OLP seems to have some potential to drive the development of OSCC in a minority of patients. However, the risk factors for such change are largely unknown—and do not presently include HPV. If the malignant potential of OLP was caused by inflammation-driven genetic and/or epigenetic change, it might be expected that lupus-like disease would increase the risk of OSCC and OED—and, indeed, there are some, all be it limited, data to support this notion.
      • Liu W.
      • Shen Z.Y.
      • Wang L.J.
      • et al.
      Malignant potential of oral and labial chronic discoid lupus erythematosus: a clinicopathological study of 87 cases.
      Similarly, as lichenoid lesions of graft-versus-host disease (GvHD) may have some malignant potential, it is probable that some types of longstanding inflammation within the oral mucosa may drive the evolution of PPOELs and later epithelial malignancy.
      • Kruse A.L.
      • Gratz K.W.
      Oral carcinoma after hematopoietic stem cell transplantation—a new classification based on a literature review over 30 years.
      • Bodner L.
      • Manor E.
      • Friger M.D.
      • van der Waal I.
      Oral squamous cell carcinoma in patients twenty years of age or younger—review and analysis of 186 reported cases.
      An inflammation-driven process might also explain the rare instances of OSCC (and presumably prior OED) in hereditary epidermolysis bullosa.

      Systemic sclerosis (scleroderma)

      Patients with scleroderma (systemic sclerosis) are at risk of a variety of malignancies, and there is some evidence that this may include the risk for OSCC.
      • Jacobsen S.
      • Halberg P.
      • Ullman S.
      Mortality and causes of death of 344 Danish patients with systemic sclerosis (scleroderma).
      A meta-analysis of observational studies showed a standardized incidence ratio for overall incidence of cancer as 1.41.
      • Onishi A.
      • Sugiyama D.
      • Kumagai S.
      • Morinobu A.
      Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies.
      A nationwide study in Taiwan
      • Kuo C.F.
      • Luo S.F.
      • Yu K.H.
      • et al.
      Cancer risk among patients with systemic sclerosis: a nationwide population study in Taiwan.
      reported a cancer incidence of 6.9 per 1000 person-years in 2053 individuals with scleroderma, and notably the oral cavity and pharynx were the second most prevalent sites (n = 11) after the lungs (n = 21). In the United States, a prospective study of 769 patients with scleroderma, representing 3775 patient-years, found 9 instances of tongue OSCC. The standardized ratio for tongue OSCC was 25 times higher than that expected in an age-adjusted population from an official US cancer registry.
      • Derk C.T.
      • Rasheed M.
      • Spiegel J.R.
      • Jimenez S.A.
      Increased incidence of carcinoma of the tongue in patients with systemic sclerosis.
      In another study, the same group reported 90 cases of cancer among this same cohort of individuals with systemic sclerosis, pointing to an overall increase in the incidence of cancer with a marked increase in the rate of esophageal and oropharyngeal malignancies.
      • Derk C.T.
      • Rasheed M.
      • Artlett C.M.
      • Jimenez S.A.
      A cohort study of cancer incidence in systemic sclerosis.
      It has been speculated that the carcinogenic potential of scleroderma may be associated with chronic inflammation, disease-related immunosuppression, or treatment.
      • Olesen A.B.
      • Svaerke C.
      • Farkas D.K.
      • Sørensen H.T.
      Systemic sclerosis and the risk of cancer: a nationwide population-based cohort study.
      It could, of course, reflect an increased permeability to carcinogens via the atrophic epithelium, or immunodeficiency-related HPV infection (hence explaining the tongue or pharyngeal tumors).

      Genetic disease

      As might be expected, disorders that cause dysregulation of DNA metabolism of the oral epithelium may give rise to PPOELs and/or OSCC. Dyskeratosis congenita (Zinsser-Engman-Cole syndrome) is a rare genetically determined disorder associated with abnormal telomere length.
      • Martinez P.
      • Blasco M.A.
      Telomere-driven diseases and telomere-targeting therapies.
      It is clinically characterized by cutaneous hyperpigmentation, nail dystrophy, oral leukoplakia, and progressive bone marrow failure.
      • Touzot F.
      • Le Guen T.
      • de Villartay J.P.
      • Revy P.
      Dyskeratosis congenita: short telomeres are not the rule.
      White patches, usually referred to in the relevant literature as leukoplakias, develop in childhood and are eventually present in over 80% of patients.
      • Vulliamy T.J.
      • Marrone A.
      • Knight S.W.
      • Walne A.
      • Mason P.J.
      • Dokal I.
      Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation.
      • Fernandez Garcia M.S.
      • Teruya-Feldstein J.
      The diagnosis and treatment of dyskeratosis congenita: a review.
      The exact histopathology of these white patches has rarely been described; of note, although they may initially have no features of OED, patients (both children and adults) have a high risk of OSCC—1000 times greater than that in non-affected individuals.
      • Martinez P.
      • Blasco M.A.
      Telomere-driven diseases and telomere-targeting therapies.
      Bloom syndrome (BS; congenital telangiectatic erythema) is a rare autosomal recessive disorder of DNA helicase function and is characterized by sun sensitivity, telangiectatic erythema of the face, and stunted growth.
      • Arora H.
      • Chacon A.H.
      • Choudhary S.
      • et al.
      Bloom syndrome.
      Up to 20% of the patients with BS develop cancer any time during their lifetime, and the most common cancers include lymphomas, leukemia, oral/esophageal squamous cell carcinoma, and adenocarcinoma of the colon.
      • Seif A.E.
      Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis.
      • Amor-Gueret M.
      Bloom syndrome, genomic instability and cancer: the SOS-like hypothesis.
      Fanconi anemia (FA) is characterized by a mutation in one of 20 involved genes leading to chromosomal instability and defects in DNA repair.
      • Savage S.A.
      • Dufour C.
      Classical inherited bone marrow failure syndromes with high risk for myelodysplastic syndrome and acute myelogenous leukemia.
      • Pivovar A.
      • Furquim C.P.
      • Bonfim C.
      • Torres-Pereira C.C.
      Mouth examination performance by children's parents and by adolescents in Fanconi anemia.
      • Kutler D.I.
      • Patel K.R.
      • Auerbach A.D.
      • et al.
      Natural history and management of Fanconi anemia patients with head and neck cancer: a 10-year follow-up.
      FA gives rise to progressive bone marrow failure, skeletal and cutaneous anomalies, and a significantly increased risk of malignancies, particularly head and neck squamous cell carcinoma.
      • Pivovar A.
      • Furquim C.P.
      • Bonfim C.
      • Torres-Pereira C.C.
      Mouth examination performance by children's parents and by adolescents in Fanconi anemia.
      • Velleuer E.
      • Dietrich R.
      • Frohnmayer A.
      • Pomjanski N.
      • Hays L.E.
      • Biesterfeld S.
      Prevalence and clinical significance of visible oral lesions in patients with Fanconi Anemia at risk for head and neck cancer.
      A study of patients from the German Fanconi Anemia Registry observed a 50-fold increase in total cancer risk with a 650-fold increase in head and neck cancer risk among patients with FA.
      • Rosenberg P.S.
      • Alter B.P.
      • Ebell W.
      Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry.
      Presumably, OSCC does not manifest de novo but is preceded by PPOELs. Of note, however, oral leukoplakias have been observed in up to 12% of children with FA before hematopoietic stem cell transplantation.
      • Grein Cavalcanti L.
      • Lyko K.F.
      • Araújo R.L.
      • Amenábar J.M.
      • Bonfim C.
      • Torres-Pereira C.C.
      Oral leukoplakia in patients with Fanconi anaemia without hematopoietic stem cell transplantation.
      Such therapy does not however, remove the risk of later PPOELs (including proliferative verrucous leukoplakia) or OSCC.
      Xeroderma pigmentosum, a rare autosomal recessive disorder of nucleotide excision repair, increases the risk of carcinomas on sun-exposed skin (and hence the lips). There have been rare instances of gingival and tongue OSCCs,
      • Bodner L.
      • Manor E.
      • Friger M.D.
      • van der Waal I.
      Oral squamous cell carcinoma in patients twenty years of age or younger—review and analysis of 186 reported cases.
      • Coulombe J.
      • Orbach D.
      • Soufir N.
      • Hadj-Rabia S.
      Primary gingival squamous cell carcinoma in a xeroderma pigmentosum type C patient.
      and presumably such genetic abnormalities first cause histopathologically evident OED, suggesting that perhaps factors other than sunlight may drive malignancy in this genetic disorder. Actinic cheilitis is a risk factor for SCC (and OED) of the lips,
      • Camara P.R.
      • Dutra S.N.
      • Takahama Júnior A.
      • Fontes K.
      • Azevedo R.S.
      A comparative study using WHO and binary oral epithelial dysplasia grading systems in actinic cheilitis.
      but there is no evidence that this ultraviolet light–driven malignant potential truly applies to intraoral epithelial surfaces).

      Hematinic and micronutrient deficiency

      Hematinic deficiency (e.g., iron, folate, or vitamin B12) can cause histopathologic and/or clinically detectable PPOELs, presumably by interfering in epithelial proliferation.
      • Theaker J.M.
      • Porter S.A.
      • Fleming K.A.
      Oral epithelial dysplasia in vitamin B12 deficiency.
      Plummer Vinson syndrome (characterized by dysphagia, iron deficiency, and esophageal webbing) can give rise to postcricoid or esophageal SCC), although there is no substantial evidence of an increased risk of OED or OSCC. In addition, such gross deficiency states are unlikely to be a common cause of PPOELs, and deficiencies of micronutrients are probably of minor importance in the development of PPOELs.
      • Madiyal A.
      • Shetty S.R.
      • Babu G.S.
      Micronutrients and their role in oral cancer: a review.

      Summary and Conclusions

      The causes or risk factors of PPOELs, in general, parallel those of OSCCs. There is relatively good evidence that tobacco and/or alcohol are drivers of OED, and it would be expected, provided appropriate research is undertaken, that oncogenic types of HPV will be of etiologic importance to the development of some PPOELs. Instances of PPOELs occasionally arise as a direct consequence of candidal infection, chronic inflammation (e.g., OLP) or dietary (or other causes of) insufficiency of hematinics, and, of course, genetically determined disease that interferes in DNA metabolism.
      For now, to improve the understanding of the long-term consequences of PPOELs, there is a need to decide whether research should be focused on disease defined at a molecular (e.g., genetic/genetic), cellular, tissue, or clinical level. Certainly, to continue to base research on clinically detectable “leukoplakia” is not justified—because the vast majority of these lesions do not represent at least histopathologically detectable cellular atypia or epithelial dysplasia. To date, knowledge has derived from research of clinically determined PPOELs, and as a consequence, the literature remains at times confusing and conflicting—which ultimately delays the development and establishment of appropriate treatment and prevention strategies.

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