sign in sign up
<<
Home , Wart

Enhanced CPD DO C OralMedicine

Michael Lewis Mouth − Risk Factors and Potentially Malignant Disorders

Abstract: The incidence of mouth cancer in the UK has increased more than 30% during the past decade and the overall 5-year survival remains poor, at approximately 55%. A number of risk factors for mouth cancer has been identified, and all dental professionals should be aware of these, and, where possible, provide intervention. Some cases of mouth cancer arise in a pre-existing mucosal condition, known as an oral potentially malignant disorder (OPMD). Awareness of the presence of an OPMD, or any mucosal changes that fulfil the criteria for urgent suspected cancer (USC) in primary care, should lead to an appropriate referral to specialist services. CPD/Clinical Relevance: This paper provides a review of the risk factors for mouth cancer and potentially malignant disorders. Dent Update 2020; 47: 793–799

The majority (90%) of malignant tumours Although to date no single factor as to directly exposed to tobacco in chewing that occur in the mouth represent why the undergoes malignant products, either alone or in combination squamous cell arising within transformation has been identified, a with other substances. More than 300 the mucosal epithelium. The incidence number of factors associated with the carcinogens have been identified in tobacco of mouth cancer is increasing in many development of mouth cancer has been smoke, in particular aromatic hydrocarbons, countries, including the United Kingdom. described (Table 1). It is essential to which when absorbed into the mucosa Unfortunately, despite improvements in investigate the presence of potential risk cause damage to replicating epithelial treatment, the 5-year survival following factors and, where possible, eliminate them. cells. Tobacco smoke and associated heat diagnosis remains poor, at approximately The dental practice setting provides an can also stimulate melanocytes in the oral 55%.1 The single most important factor ideal environment for the provision of brief mucosa and result in areas of increased that can improve the individual outcome preventive intervention for mouth cancer. pigmentation, especially in the soft is detection of the tumour whilst small, It is also important to recognize palate (Figure 2). specifically 2 cm or less in diameter with that certain mucosal abnormalities in Heat-not-burn (HNB) cigarette no regional node involvement or distant the mouth, referred to as oral potentially products have recently been developed metastases (stage I). Patients with a tumour malignant disorders (OPMDs), are known to by tobacco companies and promoted as detected at stage I are associated with an have an increased incidence of malignant an alternative to traditional smoking, with 85% 5-year survival, compared to those transformation. These OPMDs, and any a reduction in the intake of carcinogenic with stage IV (greater than 4 cm in diameter other mucosal abnormality noted during substances. In these devices, the tobacco is with regional node involvement and a routine oral soft tissue examination, warmed enough to produce a vapour but possible distant metastasis), for whom the require full assessment and management. not actually burnt. The health risks of HNB 1,2 5-year survival is only 10%. It is essential that an appropriate referral is products remain uncertain, but are known to made if the clinical findings fulfil the criteria still deliver harmful carcinogens to the user. represents epithelial cell turnover that for urgent suspected cancer (USC). Details of any tobacco habit, is out of normal control (Figure 1). such as number of cigarettes smoked daily Risk factors or number of grams of tobacco used in ‘roll- ups’ per week, should be recorded as part Tobacco of the patient’s social history. All patients Michael Lewis, PhD, FDS RCPS, FDS RCS, Tobacco usage has traditionally been with a tobacco habit should be advised FRCPath, FFGDP(UK), FHEA, Professor regarded as a prime risk factor for mouth on the increased risk of developing mouth of Oral Medicine, School of Dentistry, cancer.3 Whilst predominantly used in the cancer. Smokers who do not drink alcohol Cardiff University CF14 4XY, UK. form of cigarettes, the can be have a two-fold risk of developing mouth November 2020 DentalUpdate 793 OralMedicine

Tobacco smoking a the oral mucosa produces characteristic pigmentation changes (Figure 3). The Smokeless tobacco habit is associated with a three-fold 6 Betel quid increase in mouth cancer. It has also been implicated in the development of Alcohol , a condition also Genetics associated with mouth cancer. All patients with a betel chewing habit should be given advice to quit. light Human Alcohol Alcohol is a well recognized risk factor b Previous mouth cancer for mouth cancer.7 Consumption of Table 1. Risk factors associated with alcohol in the UK is increasing. Although mouth cancer. is not regarded as carcinogenic, its implication in mouth cancer is due to its metabolism by alcohol dehydrogenase to acetaldehyde (ACH). A number of mechanisms by which ACH causes carcinogenesis in the oral epithelium have been proposed, including disruption of DNA synthesis and repair.7 There is a two- fold increased risk of mouth cancer in Figure 3. (a, b) Mucosal pigmentation associated individuals who drink but do not smoke 4 with chewing of betel quid. tobacco. However, it is also known that ethanol can act as a solvent and increase Figure 1. Squamous cell carcinoma on the lateral absorption of carcinogens into the margin of the tongue. mucosa. This in part explains the five-fold within one year of quitting.5 The use of increase in mouth cancer in individuals conventional cigarettes is declining in who smoke tobacco and consume more developed countries due to public health than three alcoholic drinks per day.4 measures, which should hopefully lead to a Details of alcohol consumption reduction in tobacco-related mouth cancer. should be taken as part of the social Most forms of smoking cessation history. Traditionally, this has comprised are based on nicotine replacement therapy. recording the number of units of alcohol Nicotine-containing products are available drunk per week. The advice is that there as chewing gum, oral and nasal sprays, sub- should be a maximum of 14 units per lingual lozenges, inhalators and transdermal week with at least two alcohol-free days patches. More recently, electronic cigarettes in that period. It has been proposed that have become popular as a method of a Modified Single Alcohol nicotine replacement, and the associated Question (M-SASQ) is more useful than Figure 2. Pigmentation in the palate associated 95% reduction in harm compared to asking the number of units per week.8 with smoking habit. cigarette smoking has gained professional The M-SASQ consists of the following support. However, it is important to advise question, ‘How often do you have six or patients that the preferred option is to more standard drinks on one occasion?’ cancer, which increases with frequency and quit completely. Never, less than monthly, monthly, weekly, duration.4 The use of smokeless products, or daily or almost daily. A positive score such as powdered snuff or chewing Betel quid is any option other than never or less tobacco, also carry similar risks. The chewing of betel quid, which is a than monthly. Patients with a positive All patients should be advised mixture of areca nut with other substances, score should be advised to contact on the association of a tobacco habit with such as lime and tobacco, wrapped in a local support services to help with a negative impact on health. Advice on betel leaf, is popular in south and south- alcohol addiction. contact details of a local cessation service east Asia. It is also used by communities should be provided, in particular to those from these regions in other parts of the Genetic factors patients who express a wish to quit. A world, including the UK. The placement There is some evidence that genetic risk reduction has been demonstrated of the betel quid in direct contact with variants involving alcohol metabolism 794 DentalUpdate November 2020 OralMedicine

four or more oral sex partners. Interestingly, HPV-associated squamous cell carcinoma in the oropharynx has a better prognosis than conventional non-HPV-infected cancer.11 It is thought that HPV-positive tumours have less genomic damage and field change and, as such, respond better to a combination of radiotherapy and .11 Vaccination programmes for HPV-16 and HPV-18 are now available in many countries and this should be given Figure 6. HPV-positive oropharyngeal squamous to both boys and girls at the age of cell carcinoma. 11−12 years.

Leukoplakia Ultraviolet light Chronic exposure to ultraviolet (UV, mainly UVB) in sunlight, often as part of Palatal changes in reverse smokers an outdoor occupation, increases the risk of developing actinic (solar) and Oral submucous fibrosis Figure 4. in dyskeratosis congenita cancer of the lower lip. Protective sun- (Courtesy of Professor G Ogden). blocking agents (SPF 15 or greater) should be recommended. a Discoid erythematosus Previous mouth cancer Hereditary disorders with increased risk A patient who has been diagnosed and successfully treated for mouth cancer needs Table 2. Potentially malignant disorders of the close review, since such an individual is at oral mucosa.12 an increased risk of developing a further (new primary) mouth cancer.

Immunosuppression Potentially malignant The development of mouth cancer has conditions b been described in association with the use The majority of cases of SSC in the mouth of immunosuppressive drugs, in particular arise in what was previously clinically 9 as an aspect of solid organ transplantation. normal tissue. However, some Renal transplant patients may develop a are known to develop within a pre- leukoplakia, some of which develop into existing mucosal abnormality and a list mouth cancer (Figure 5). Reduction in the of such conditions was published in 2007 immunosuppressive therapy can lead to (Table 2).12 reduced incidence of cancer.10

Leukoplakia Figure 5. Renal transplant patient with a Human papilloma virus The most frequently recognized OPMD leukoplakia (a) that underwent malignant There are more than 100 types of human is leukoplakia (Figure 7), which was first transformation (b). papilloma virus (HPV), some of which defined by the WHO in 1978 as ‘a white are associated with the development of patch or plaque that cannot be characterised malignancy at different body sites. In recent clinically or pathologically as any other years, it has been recognized that HPV disease’.13 The term has subsequently been and DNA repair pathways are risk factors 16 is involved in oropharyngeal cancer. refined following various international for mouth cancer and a hereditary family It is important to appreciate that HPV is workshops and is now used to describe history has been described.5 In addition, implicated in oropharyngeal cancer rather ‘white plaques of questionable risk having some genetic conditions, for example than mouth cancer (Figure 6). The virus excluded (other) known diseases and dyskeratosis congenita, are known to is sexually transmitted and, although the disorders that carry no increased risk for be associated with increased incidence natural history of oral HPV is not cancer’.14 It is essential to remember that of cancer and should be managed as an well understood, there is increased oral leukoplakia is a clinical term and not a OPMD (Figure 4). carriage of the virus in individuals who have diagnosis. A biopsy is required to exclude November 2020 DentalUpdate 795 OralMedicine

malignant transformation rate for oral mucosal conditions in the population, leukoplakia has ranged from low levels with a reported prevalence of between of 0.13% in India15 and 2.6 % in the UK,16 0.5% and 2.2%.22 Different types of OLP to high levels of 17.5% in USA.17 These have been described, including reticular, findings are undoubtedly influenced atrophic, erosive, plaque-like and bullous, by the geographical site, population based on the appearance of the mucosa. studied, number of patients and length However, actual typing in an individual of follow-up observation period. The patient is often difficult, since different global malignant transformation rate of types may be present simultaneously and leukoplakia is generally accepted to be also change during the course of disease 1.36% per year.18 over months. Figure 7. Leukoplakia in the floor of the mouth. There is a rare form of Overall, the most leukoplakia, termed proliferative characteristic feature is the presence (PVL), which has of bilateral white striations in the a reported transformation rate as high buccal mucosa (Figure 9). The reported as 70%.19 The presentation of PVL is malignant transformation for OLP characterized by an initial white patch worldwide has varied between 0.4% that develops into multiple areas of and 6.4%, depending on the population exophytic/wart-like changes within studied and length of follow-up period. the mucosa. The aetiology of PVL is Two historical UK-based studies revealed unknown and treatment is difficult due yearly transformation rates of 0.07% and to progressive recurrence following 0.27%.23,24 A recent systematic review surgical removal. revealed an increased transformation risk with erythematous forms on the tongue 25 Figure 8. Erthroplakia in the floor of the mouth. Erythroplakia (Figure 10). Oral erythroplakia (Figure 8) is a defined as ‘a fiery red patch that Submucous fibrosis cannot be characterised clinically or Submucous fibrosis is a chronic disorder pathologically as any other definable of the upper alimentary tract, which lesion’.20 Erythroplakia, in a similar presents most obviously within the way to leukoplakia, has no specific mouth as vertical fibrous bands in the histopathological features. The term is buccal mucosa that limit mouth opening. used clinically to record the presence of The patient will also complain of an an erythematous mucosal abnormality overall burning sensation within the that does not have a clinical appearance mouth, including the buccal mucosa, characteristic of known red patches, which may appear white or erythematous such as denture-associated candidosis (Figure 11). Oral submucous fibrosis b or median rhomboid . (OSF) has a strong association with the Oral erythroplakia has the highest social habit of chewing areca (betel) transformation rate of all of the nut, which is popular in populations OPMDs, being reported as between living in and originating from the Indian 14% and 50%.21 Erythroleukoplakia is subcontinent and surrounding countries. an alternative clinical term that can be Alkaloids within the nut stimulate used when the mucosa has a speckled fibroblast proliferation. The malignant red and white appearance. Importantly, transformation rate from a long-term erythroleukoplakia is associated with a follow-up study of OSF in an Indian high risk of malignant change. population was reported as 7.6%.26 Figure 9. (a , b) Bilateral lichen planus in the buccal mucosae. Lichen planus Palatal keratosis in reverse smokers The aetiology of oral lichen planus Reverse smoking, in which the lit end (OLP) is unknown but does involve of a cigar or cigarette is placed in the known mucosal disorders that may the immune system, since a primary mouth, is popular in the rural populations present as a white patch. Although often histopathological feature is a sub- of the Amazon, New Guinea and Indian associated with the presence of epithelial epithelial band of T lymphocytes, subcontinent. The physical irritation from , leukoplakia itself has no specific indicating a cell-mediated reaction. OLP heat and tobacco smoke induces hyper- histopathological features. The reported is one of the most frequently occurring keratinization and erythematous changes 796 DentalUpdate November 2020 OralMedicine

a a

Figure 11. White patches in buccal mucosa and b restricted mouth opening in submucous fibrosis.

b Figure 13. (a, b) Chronic hyperplastic candidosis as bilateral white patches.

Figure 12. Squamous cell carcinoma arising in previous actinic keratosis. regions of the mouth (Figure 13) or dorsum of the tongue. This type of oral candidosis is seen almost exclusively in smokers. Although biopsy to exclude transformation into the provision of systemic antifungal either a squamous cell carcinoma or basal therapy will produce a dramatic clinical cell carcinoma (Figure 12). The actual improvement (Figure 14), the mucosal transformation rate of actinic keratosis changes will recur if the patient does is unknown. not stop the tobacco habit.

Discoid lupus erythematous Urgent suspected Discoid , which cancer referral can produce oral mucosal changes that resemble oral lichen planus or The outcome of mouth cancer is erythroplakia, has been reported to significantly improved if the tumour transform into squamous cell carcinoma. is detected and treated when it is less Figure 10. Lichen planus (a) that underwent than 2 cm in diameter with no local malignant transformation (b). metastasis. On this basis, any patient Dyskeratosis congenita suspected to have cancer should Dyskeratosis congenita, which is an be referred as a USC for specialist inherited genetic-based OMPD, is a bone assessment rapidly with an expectation within palatal mucosa. A high incidence marrow disorder that is associated with that they will be seen within 14 days of cancer in the hard palate, which is a oral leukoplakia and mouth cancer that (2-week wait, 2WW) or 10 working days 28 relatively rare site in non-reverse smokers, can cause death in young adulthood. (10-day rule).1 The 2WW system for 27 has been associated with this habit. cancer, including , Other conditions was introduced in the UK in 2000. The Actinic keratosis Although not included in the WHO National Institute for Health and Clinical Actinic keratosis is associated with exposure list of OPMDs, chronic hyperplastic Excellence (NICE)30 and Healthcare to ultraviolet light and characteristically candidosis (CHC) is recognized as having Improvement Scotland (HIS)31 have affects the lower lip presenting as the potential to undergo malignant published referral guidelines to help palpable white plaques. Regular review is transformation.29 CHC characteristically clinicians decide which patients should required and the development of palpable presents as bilateral adherent white be referred as USC. These guidelines induration would indicate the need for patches in the buccal commissure focus on the presenting clinical November 2020 DentalUpdate 797 OralMedicine

a  Unexplained ulceration in the oral cavity lasting more than 3 weeks  A persistent and unexplained lump in the neck  A lump on the lip or in the oral cavity consistent with oral cancer  A red or red and white patch in the oral cavity consistent with erythroplakia or erythroleukoplakia Table 3. Potentially malignant disorders of the mucosa.12 b in not only USC but routine referrals, with the potential for malignant change. has to be recommended, since this Knowledge and application of the USC is extremely useful to the clinician in referral pathway is an essential aspect of vetting the urgency of any referral. primary care dentistry. Methods of referral from primary care to specialist secondary Compliance with ethical standards care vary widely. Historically, referrals Informed consent was obtained from all have been made in the form of a written patients for the clinical images used in letter with inevitable risk of delay within this article. a postal system. Electronic record Figure 14. Chronic hyperplastic candidosis at management and referral systems within References presentation (a) and improvement after 7 days of managed clinical networks (MCNs) systemic fluconazole (b). are being introduced and these have 1. www.cancerresearchuk.org a range of advantages, including an (accessed September 2020). assurance of rapid and safe delivery 2. Sciubba JJ. Oral cancer. The of the referral request. In addition, importance of early diagnosis and symptoms (Table 3). some electronic systems ensure that treatment. Am J Clin Dermatol 2001; An audit of the 2WW rule all relevant information is provided 2: 239−251. in the Oral and Maxillofacial by the referring practitioner, since 3. Pemberton MN. Oral cancer and department at the Newcastle General the referral will not be accepted until tobacco: developments in harm Hospital, and then subsequently in this is completed online. Individual reduction. Br Dent J 2018; 225: the Oral Surgery and Oral Medicine practitioners must be aware of their local 822−826. https://doi.org/10.1038/ departments at Newcastle Dental referral system. sj.bdj.2018.928. Hospital, revealed positive head and One unfortunate impact 4. Hashibe M, Brennan P, Chuang SC neck cancer detection rates of 11% of early lockdown restrictions of the et al. Interaction between tobacco and alcohol use and the risk of head and 7%, respectively, in the cohorts of COVID-19 pandemic was the significant 32 and neck cancer: pooled analysis patients examined. A similar study reduction in the number of USC referrals in the International Head and Neck at the Oral Medicine department in from both dental and medical primary Cancer Epidemiology Consortium. King’s College, London, reported that care.35 Although the referrals are coming Cancer Epidemiol Biomarkers Prev 8% of urgent referrals were found through the system again now, there has 33 2009; 18: 541−550. https://doi. to have oral cancer. Both audits undoubtedly been a delay in diagnosis org/10.1158/1055-9965.EPI-08-0347. concluded that further education for some patients with an inevitable 5. Conway DI, Purkayastha M, Chestnutt of referring practitioners and adverse impact on their outcome. refinement of the referral guidelines IG. The changing epidemiology of were required to ensure a more oral cancer: definitions, trends, and efficient service. Conclusion risk factors. Br Dent J 2018; 225: One aspect of referral that Although the aetiology of mouth 867−873. https://doi.org/10.1038/ can be improved is avoidance of the cancer remains unknown, a number sj.bdj.2018.922. term ‘lesion’. The word lesion derives of risk factors have been found for the 6. Gupta B, Johnson NW. Systematic from the Latin term laesio meaning development of this form of malignancy. review and meta-analysis of injury and, as such, is non-specific. It is Some of these factors are modifiable association of smokeless tobacco far more helpful to use the descriptive and patients should be provided and of betel quid without tobacco words such as , swelling or red with appropriate advice in primary with incidence of oral cancer in patch in the clinical records and any dental care. In addition, all members South Asia and the Pacific. PLoS referral communication.34 In addition, of the dental team should be aware of One 2014; 9: e113385. https://doi. the inclusion of clinical photographs, mucosal changes that are associated org/10.1371/journal.pone.0113385. . 798 DentalUpdate November 2020 OralMedicine

7. Ogden GR. Alcohol and mouth period in south east England. J Oral 29. Williams DW, Bartie KL, Potts AJC, cancer. Br Dent J 2018; 225: Pathol Med 2011; 40: 677−683. Wilson MJ, Fardy MJ, Lewis MAO. 880−883. https://doi.org/10.1038/ 17. Silverman S, Gorsky M, Lozada F. Strain persistence of invasive sj.bdj.2018.921. Oral leukoplakia and malignant Candida albicans in chronic 8. Roked Z, Watson R, Moore S, transformation: a follow up study hyperplastic candidosis that Shepherd J. Identification of of 257 patients. Cancer 1984; 53: underwent malignant change. alcohol misuse in dental patients. 563−568. Gerodontology 2001; 18: 73−78. Fac Dent J 2014; 5: 134−137. 18. Petti S. Pooled estimate of world 30. National Institute for Health and https://doi.org/10.1308/20426851 leukoplakia prevalence: a systematic Care Excellence. Suspected cancer: 4X14017784506050. review. Oral Oncol 2003; 39: 770−780. recognition and referral. 23 June 9. Öhman J, Rexius H, Mjörnstedt L et 19. Munde A, Karle R. Proliferative 2015. www.nice.org.uk/guidance/ al. Oral and lip cancer in solid organ verrucous leukoplakia: an update. transplant patients. A cohort study J Can Res Ther 2016; 12: 469−473. ng12 (accessed September 2020). from a Swedish Transplant Centre. 20. Pinborg JJ, Reichart Smith CJ, van 31. Healthcare Improvement Scotland. Oral Oncol 2015; 51: 146−150. der Waal I, Sobin LH and pathologists Scottish Referral Guidelines 10. Lewis MAO et al. Development of in nine countries. World Health for Suspected Cancer. www. multiple oral cancers in a renal Organization International Histological healthcareimprovementscotland. transplant associated leukoplakia. Classification of Tumours, Histological org/our_work/cancer_care_ Dent Health 2013; 52: 20−23. Typing of Cancer and Precancer of the improvement/programme_ 11. Speight PM, Farthing PM. The Oral Mucosa 2nd edn. Berlin: Springer, resources/scottish_referral_ pathology of oral cancer. Br Dent 1997. guidelines.aspx (accessed J 2018; 225: 841−847. https://doi. 21. Reichart PA, Philipsen HP. Oral September 2020). org/10.1038/sj.bdj.2018.926. erythroplakia − a review. Oral Oncol 32. Miller CC, Hierons RJ. Two audits of 12. Warnakulasuriya S, Johnson NW, 2005; 41: 551−561. the diagnosis of oral cancer and the van der Waal I. Nomenclature 22. De Rossi SS, Ciarrocca K. Oral lichen two-week rule following referrals and classification of potentially planus and lichenoid mucositis. Dent from primary care practitioners in malignant disorders of the oral Clin North Am 2014; 58: 299−313. Newcastle. Prim Dent Care 2012; 19: mucosa. J Oral Pathol Med 2007; 36: 23. Rajentheran R, McLean NR, Kelly 63−68. 575−580. https://doi.org/10.1111/ CG, Reed MF, Nolan A. Malignant 33. Singh P, Warnakulasuriya S. The j.1600-0714.2007.00582.x. transformation of oral lichen planus. two-week wait cancer initiative on 13. Kramer IRH, Lucas RB, Pindborg Eur J Surg Oncol 1999; 25: 520−523. JJ, Sobin LH and World Health 24. Ingafou M, Leao JC, Porter SR, Scully oral cancer; the predictive value of Organization Collaborating Center C. Oral lichen planus: a retrospective urgent referrals to an oral medicine for Oral Precancerous Lesions. study of 690 British patients. Oral Dis unit. Br Dent J 2006; 201: 717−720. Definition of leukoplakia and 2006; 12: 463−468. 34. Lewis MAO. Mouth cancer − What related lesions. An aid to studies on 25. Giuliani M, Troiano G, Cordaro M et al. is it to you? Br Dent J 2018; 225: oral precancer. Oral Surg Oral Med Rate of malignant transformation of 789−790. Oral Pathol 1978; 46: 518−539. oral lichen planus: a systematic review. 35. Lewis M, Thomas C. USC referrals. 14. Warnakulasuriya S, Johnson N Oral Dis 2019; 25: 693−709. https://doi. Br Dent J 2020: 228: 657−658. W, van der Waal I. Nomenclature org/1111/odi.12885. and classification of potentially 26. Murti PR, Bhonsle RB, Pindborg JJ, malignant disorders of the oral Daffary DK, Gupta PC, Mehta FS. mucosa. J Oral Pathol Med 2007; 36: Malignant transformation rate in oral CPD ANSWERS 575−580. submucous fibrosis over 17 period. 15. Silverman S, Bhargava, K, Smith Community Dent Oral Epidemiol 1985; September 2020 LW, Malaowalla AM. Malignant 13: 340−341. transformation and natural history 27. Gupta PC, Mehta FS, Daftary DK et 1. B 6. C of oral leukoplakia in 57,518 al. Incidence rates of oral cancer and industrial workers of Gujarat, India. natural history of oral precancerous Cancer 1976; 38: 1790−1795. lesions in a 10-year follow up study of 2. A 7. C 16. Warnakulasuriya S, Kovacevic Indian villagers. Community Dent Oral T, Madden P, Coupland VH, Epidemiol 1980; 8: 287−333. 3. D 8. C Sperandio M, Odell E, Møller H. 28. Ogden GR, Connor E, Chisholm DM. Factors predicting malignant Dyskeratosis congenita: report of a 4. C 9. A transformation in oral potentially case and review of the literature. Oral malignant disorders among Surg Oral Med Oral Pathol 1988; 65: 5. D 10. C patients accrued over a 10-year 586−591. November 2020 DentalUpdate 799