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Leukoplakia of the maxillary vestibule—an association with Viadent?
Vol. 87 No. 1 January 1999
ORAL SURGERY, ORAL MEDICINE, ORAL PATHOLOGY,
ORAL AND MAXILLOFACIAL PATHOLOGY
Editor: Carl M. Allen
Leukoplakia of the maxillary vestibule—an association with Viadent? Douglas D. Damm, DDS,a Alice Curran, DMD, MS,b Dean K. White, DDS, MSD,a and James F. Drummond, MSD, DDS, PhD,a Lexington, Ky, and Jackson, Miss UNIVERSITY OF KENTUCKY AND UNIVERSITY OF MISSISSIPPI
Objective. This report investigates a possible correlation between chronic use of Viadent products and the subsequent development of leukoplakia in the maxillary vestibule.
Study design. A retrospective review of 88 patients with leukoplakia of the maxillary vestibule is presented. Prevalence of Viadent use was determined in this group and in a group of 100 randomly selected adults who presented themselves for routine preadmission screening at a dental school. Results. Of the patients diagnosed with leukoplakia of the maxillary vestibule, 84.1% reported having used Viadent, whereas the prevalence of use was only 3% in the 100 randomly selected adults. Conclusions. Use of Viadent products appears to be associated with an increased prevalence of leukoplakia in the maxillary vestibule.
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:61-6)
The term Viadent refers to brand name formulations of antiplaque toothpaste and oral rinse that use sanguinaria extract, a mixture of benzophenanthridine alkaloids derived from the common bloodroot plant, Sanguinaria canadensis L.1 These oral products, which have shown an antibacterial, antifungal, and anti-inflammatory activity, were introduced in 1982 by Vipont Pharmaceuticals and are currently marketed by Colgate Oral Pharmaceuticals. In April 1990, Vipont organized a symposium in Toronto to review and present research related to the safety and effectiveness of sanguinaria and Viadent products. A thorough review of the previous clinical trials of sanguinaria-containing toothpaste and oral rinses was presented; the review supported a related significant reduction in supragingival plaque, gingival inflammation, and bleeding without adverse mucosal or hard tissue effects.2 A similar thorough evaluation of the toxicity and carcinogenicity was performed, and it aProfessor, Division of Oral & Maxillofacial Pathology, College of Dentistry, University of Kentucky. bAssistant Professor, Department of Diagnostic Sciences, School of Dentistry, University of Mississippi. Received for publication July 2, 1998; returned for revision July 24, 1998; accepted for publication Sept. 2, 1998. Copyright © 1999 by Mosby, Inc. 1079-2104/99/$8.00 + 0 7/14/94688
was concluded that Viadent products exhibit a large margin of safety without any significant danger when they are used as directed in the currently marketed forms of toothpaste and oral rinse.3 Although previous studies 2 decades earlier had suggested a carcinogenic potential,4 the weaknesses in these evaluations were highlighted, and the carcinogenicity was not corroborated on review.3 In addition, the mutagenic potential of sanguinarine was studied in a previous report and found by the Ames test to be negative.5 Although the medical literature often presents a rather clear picture of many controversial topics, information gained from daily patient care also exposes problems previously hidden to the scientific community. This report documents such a discovery.
PATIENT PROFILES Each of 2 patients of a contributing oral surgeon had appeared for treatment with an isolated area of leukoplakia in the maxillary vestibule. Incisional biopsy of the lesions revealed mild epithelial dysplasia. Neither patient used tobacco products or abused alcohol. One of the patients firmly believed that the appearance of her lesion was secondary to her use of Viadent rinse and toothpaste. The second patient was questioned, and she too revealed a positive history of Viadent use. At this point, the surgeon contacted his oral and maxillo61
62 Damm et al
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY January 1999
Fig 1. Discrete leukoplakia of left maxillary facial gingiva that extends onto adjacent alveolar mucosa to depth of vestibule.
Fig 3. Large leukoplakia of anterior maxillary vestibule that extends onto adjacent buccal mucosa. Focal area of erythema on right side represents healing biopsy site.
Fig 2. Focal area of corrugated leukoplakia of right maxillary facial gingiva and alveolar mucosa.
facial pathologist and requested a review of this possible association. Over the next few months, biopsies from several patients who had similar profiles were received; the involved patients also revealed use of Viadent. With the number of newly presented cases enlarging, a search of the last 5 years’ accessions for every biopsy diagnosed as epithelial dysplasia from the maxillary vestibule was performed in an attempt to evaluate previously submitted specimens. Only leukoplakias localized to a discrete zone of the facial maxillary gingiva or the alveolar mucosa between the mucogingival junction and the depth of the vestibule were included (Figs 1, 2, and 3). Extension of the leukoplakia onto the adjacent buccal or labial mucosa was allowed, but patients exhibiting involvement isolated to these 2 locations were excluded. On discovery of the appropriate clinical history, the involved contributor was requested to contact the patient and ask several simple questions; these pertained to prior or present use of Viadent, form and duration of use (if any), and history of tobacco and alcohol consumption.
During this period of time, all new patients appearing for evaluation and treatment of leukoplakias of the maxillary vestibule were questioned in a similar fashion. As a result of a suggestion from representatives of Colgate Oral Pharmaceuticals, the data collection design for newly discovered patients was changed. All future patients were presented with a questionnaire that requested them to identify their current and past oral hygiene products in a list of 12 different toothpastes and 10 different oral rinses, the names of which were arranged in alphabetic order. In addition, the same questionnaire was submitted randomly to 100 patients over 35 years of age who came to the institution of the initiating oral pathologist for routine preadmission screening. An initial group of 80 patients did not use the questionnaire; of these, follow-up could not be obtained from 20. Of the remaining 60 patients, 49 (81.7%) had positive histories of Viadent use. Subsequently, 30 additional patients were identified from newly submitted specimens. To discover the prevelance of Viadent use, this latter group was given the same questionnaire presented to the 100 preadmission patients. Of these 30 patients, 2 did not complete the questionnaire, 3 did not use Viadent, and 25 (89.3%) were positive for Viadent use. Despite the concerns of the Colgate representatives, the questionnaire did not appear to significantly alter the prevalence rate of Viadent use; therefore, the 2 groups have been combined for analysis. With the 2 groups combined, a history of Viadent use was sought from each of a total of 110 patients with leukoplakia of the maxillary vestibule; sufficient followup was obtained from 88 patients. The prevalence of Viadent use in this group is illustrated in Fig 4. The results of the questionnaire randomly administered to the 100 preadmission patients are presented in Fig 5. Of the 3 patients using Viadent, 2 were husband and wife; therefore, the true prevalence could be somewhat lower.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 87, Number 1
Damm et al 63
Fig 4. Prevalence of Viadent use in a group of 88 patients with leukoplakia of maxillary vestibule. Fig 6. Age and gender distribution of patients with leukoplakia of maxillary vestibule and positive history of Viadent use.
Fig 5. Prevalence of Viadent use in a group of 100 patients more than 35 years of age and chosen at random.
All of the patients with histories that were positive for Viadent use were Caucasian; they demonstrated an age range from 38 to 89 years, with a mean age of 60.8 years. The age and gender distribution is presented in Fig 6, with the form of Viadent use illustrated in Fig 7. The duration of use varied from 6 months to 12 years, with a mode of 5 years and a mean of 4.4 years. Fig 8 illustrates the history of tobacco and alcohol use. No tobacco use was noted in 66.2% of the patients. Although 40.9% reported alcohol use, consumption on a regular basis was documented in only 7% of the patients. Histopathologically, the biopsies removed from Viadent users demonstrated remarkable similarity, often allowing the pathologist to predict the history before reviewing the associated patient information. Fig 9 delineates the most commonly noted features, together with the prevalence of these alterations. All cases demonstrated hyperorthokeratosis; mixture with hyperparakeratosis was noted in 11 examples. Seventy-three of the 74 cases demonstrated mild levels of epithelial dysplasia. In 40 of these 73 cases, the dysplastic alterations were minimal (increased cellularity and hyperchromatism of the basilar one third) and represented a borderline level of dysplasia; in 31 of the remaining 33 cases, definitive mild dysplasia was evident, and in 2 cases the dysplasia was moderate in severity. Although mucositis was present almost consistently, the levels were mild in all but 2 cases; in
these 2 cases, the mucositis was moderate in intensity. Although a verruciform surface was present in a significant percentage of cases, the degree of this alteration was minimal in all but 3 cases. In addition to these common findings, melanosis was noted histopathologically in 8 cases and acanthosis in 3 cases. Fig 10 delineates the histopathologic features of a typical lesion. In comparison with adjacent normal mucosa, the affected epithelium is mildly atrophic and exhibits significant hyperorthokeratosis, mild chronic mucositis, and basilar hypercellularity and hyperchromatism. Fig 11 illustrates a similar specimen that is slightly more atrophic and demonstrates mild dysplasia. An example of a lesion with a mildly verruciform surface is presented in Fig 12. Follow-up was obtained from 34 of the patients diagnosed with Viadent-related leukoplakias. In these patients, the duration of follow-up from the date of initial biopsy varied from 8 to 84 months, with a mean of 33.5 months. After the initial biopsy, the lesion was excised completely or ablated with a laser in each of 19 cases; after this procedure, there was complete healing in 13 cases, with no evidence of disease. Six recurrences were seen (31.6%), with 2 ultimately resolving completely over a period of up to 28 months. The lesions in 15 patients received no further therapy after the initial biopsy. In these instances, 4 lesions resolved completely (26.7%), 6 decreased in size (40%), and 5 remained stable (33.3%). In one case, a new lesion arose after resolution of the initial leukoplakia.
DISCUSSION Unfortunately, the method of data collection changed as our study evolved; nevertheless, the association between the presence of leukoplakia in the maxillary vestibule and use of Viadent products is strong and overcomes methodologic arguments. The prevalence of Viadent use in a randomly selected population of adult patients presenting themselves for routine dental care was 3%; this compared with a prevalence of 84.1% of
64 Damm et al
Fig 7. Form of Viadent use in patients affected with leukoplakia of maxillary vestibule.
Fig 8. History of tobacco and alcohol use in patients with leukoplakia of maxillary vestibule and positive history of Viadent use.
patients in the current group affected with leukoplakia of the maxillary vestibule. Despite the thorough review of the literature presented at Vipont’s 1990 symposium in Toronto, a debate still exists with regard to the toxicity and carcinogenicity of sanguinaria. Significant relevant research related to the presence and effects of sanguinaria in certain foodstuffs is ongoing. One such foodstuff is edible oils, which constitute an integral portion of the human diet in many countries, particularly India. The shortage of edible oils prompts unscrupulous traders to adulterate the parent oil with cheaper, nonedible oils. One of these contaminants is argemone oil, which is frequently used because of its easy availability, low cost, and total miscibility with mustard oil, a popular edible oil. Consumption of these contaminated oils may give rise to a number of clinical symptoms that are collectively termed epidemic dropsy. The associated symptoms include vomiting, diarrhea, nausea, swelling of the limbs, erythema, pitting edema, and breathlessness. In severe cases, glaucoma and death secondary to cardiac failure have been reported. As recently as 1997, the toxicity of argemone has been related to its 2 physiologically active benzophenanthridine alkaloids, sanguinarine and dihydrosanguarine.6 With respect to
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY January 1999
Fig 9. Most common histopathologic findings noted in biopsies obtained from patients with leukoplakia of maxillary vestibule and positive history of Viadent use.
these 2 alkaloids, the toxicity of sanguinarine is 2.5 times greater than that of dihydrosanguinarine.7 Scientists who investigate the medical benefits and risks of numerous herbal products in the folk medicine of ethnic groups throughout the world include ethnobotanists and pharmacognosists. Early in the developmental phase of Viadent products, concerns were raised by several of these specialists regarding the safety of the chronic use of sanguinaria extract in dental rinses and toothpastes. It was recognized that health problems related to historic uses for other purposes had been associated with sanguinaria extract and sanguinarine and that potential complications might arise when such highly bioreactive molecules were used on a regular basis and accumulated in the body. In an attempt to address these issues, a number of company-sponsored toxicology studies appeared in the dental literature, and an expert panel was convened to review the results. Even though it was recommended strongly that these results be reported, none of them have appeared in toxicologic journals in which independent verification and careful peer review occur.8 In the company-sponsored review, the only study that was carried out was a 28-day oral mucosal irritancy study conducted in dogs and reported as negative.3 The panel also reviewed 908 case reports provided by consumers after use of Viadent products. In this group, the largest numbers of complaints had to do with burning and stinging in the mouth. It is possible that long-term exposure to an irritant could contribute to the product-associated pathosis documented in the current series. In addition, “weak positive” or “unequivocal” test results of mutagenicity or carcinogenicity were reported, but these were trivialized because of the results of a previous Ames test, which was negative. Inasmuch as the 2 major components of sanguinaria extract, sanguinarine and chelrythrine, are known DNA intercalators, the results of that reported Ames test are drawn into question; frameshift mutants would be expected to
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 87, Number 1
Fig 10. Typical histopathologic pattern of leukoplakia noted in patients with positive history of Viadent use. Note hyperorthokeratosis, mild epithelial atrophy, mild chronic mucositis, and basilar hypercellularity and hyperchromatism (hematoxylin-eosin, original magnification ×100).
Fig 11. Histopathologic findings of dysplastic leukoplakia of maxillary vestibule removed from patient with positive history of Viadent use. Note hyperorthokeratosis, significant epithelial atrophy, mild epithelial dysplasia, and chronic mucositis (hematoxylin-eosin, original magnification ×400).
be elicited by these types of compounds.9 In the light of accumulating data that continues to fuel this controversy, an “uncertainty factor” regarding safety remains. Although it has been discredited by many investigators (including some who were promoted by Vipont), the early work of Hakim4 on the carcinogenic potential of sanguinaria continues to draw support from several investigators.6,10 In the thorough 1997 review by Das and Khanna,6 sanguinarine and its metabolites were thought likely to be carcinogenic, even in low concentrations, possibly explaining in part the increased prevalence of esophageal and nasopharyngeal cancers in regional portions of the globe.6 Needless to say, agreement on such issues does not exist, and much work still remains incomplete.
Damm et al 65
Fig 12. Histopathologic findings of leukoplakia of maxillary vestibule that was removed from patient with positive history of Viadent use and exhibits mild verruciform surface alteration, hyperorthokeratosis, epithelial atrophy, basilar hyperplasia, and chronic mucositis (hematoxylin-eosin, original magnification ×100).
Are the Viadent-related leukoplakias precancerous? As discussed, uniform agreement on the carcinogenicity of sanguinaria does not exist. The biopsies from 98.6% of the affected patients were graded as dysplastic, but only 2 of these approached a moderate degree of severity, even though approximately 40% of the patients had used the products for more than 5 years. Whether these atypical cellular changes actually represent dysplasia or simply reflect unusual reactive changes is open to question. If the materials are carcinogenic, a long preneoplastic period must exist. If such transformation is possible, it appears that decades of use would be required to document the alteration in a significant number of patients. Why did many of the leukoplakias persist after discontinuation of Viadent or recur after removal and product cessation? Although superficially this may suggest lack of association with Viadent, several important features of the alkaloid must be highlighted. Sanguinarine and its metabolites appear to alter liver metabolism, are eliminated slowly, and are retained in the gastrointestinal tract, liver, lung, kidney, and heart.11,12 Delayed retention in serum is noted and may be due to binding with plasma proteins. 13 Finally, sanguinarine demonstrates the ability to bind to natural host DNA over a wide range of environmental parameters.14,15 Can other oral mucosal sites be affected also? Of the currently reported 74 patients with leukoplakia of the maxillary vestibule, 5 also demonstrated involvement of another site outside the study area. Two of these cases involved the floor of the mouth, 1 the mandibular mucobuccal fold, 1 the buccal mucosa, and 1 the lateral border of the tongue. Because of a high index of suspicion, many clinicians are investigating Viadent use in any patient with leukoplakia and without a history of the typical high risk factors. A small number of
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ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY January 1999
histopathologically similar leukoplakias have been discovered in Viadent users without involvement of the maxillary vestibule. These patients are not included in the present study. Why did the leukoplakias cluster in the maxillary vestibule? This site was not chosen; rather, it was suggested by the surgeon whose patient made the original connection. Since that time, literature that supports the clustering has been produced.16 The perception that saliva quickly dilutes and washes away substances introduced into the mouth is not true. In many cases, such materials adhere to mucosal surfaces, become trapped between teeth, or are retained in sites where the salivary turnover is low. The highly site-specific character of oral mucosal drug delivery has not been appreciated fully by many investigators. When rinses are used, intraoral concentrations are highly variable within different regions, and dramatic differences are revealed. The concentration is noted to be significantly higher in buccal sites than in lingual sites, with the upper sulcus consistently demonstrating a higher concentration than the lower sulcus. These findings are consistent regardless of what material is being used and regardless of the manner in which the substance is introduced to the site (paste or rinse). These differential patterns can persist for hours. Of all oral locations, the anterior portions of the maxillary vestibule have the highest concentration of materials in the mouth; this is due to the distance of the vestibule from all major salivary gland ducts. Only the viscous secretions from minor salivary glands are likely to dilute materials in this area. The concentration in the mandibular vestibule will be less because of rapid dilution from submandibular and sublingual gland secretions. The lowest concentrations occur in the floor of the mouth because of high flow from the sublingual glands and submandibular glands and because of other oral fluids draining into the floor of the mouth. Therefore, as a result of prolonged retention of mouth rinses and toothpastes in the maxillary vestibule, a high prevalence of associated mucosal changes in this area is not surprising. What is appropriate therapy? Initial biopsy is mandatory. Once a histopathologic diagnosis of epithelial dysplasia is obtained, the mucosal pathosis should be treated as any other potentially premalignant process, regardless of its supposed cause, would be treated. As delineated by Neville et al,17 leukoplakia demonstrating moderate epithelial dysplasia or worse warrants eradication. The management of lesions with less severe changes should be guided by individual clinical judgment, according to the size of the lesion, and in light of the response to more conservative measures, such as discontinuation of Viadent use and cessation of any
tobacco use. The vast majority of Viadent-associated leukoplakias manifest minimal levels of dysplasia. In these cases, many clinicians choose close follow-up but no further surgery; however, if significant worsening of the clinical appearance is noted, subsequent surgery with histopathologic evaluation is mandated. REFERENCES 1. Harkrader RJ, Reinhart PC, Rogers JA, Jones RR, Wylie RE II, Lowe BK, et al. The history, chemistry and pharmacokinetics of Sanguinaria extract. J Can Dent Assoc 1990;56(7 Suppl):7-12. 2. Kuftinec MM, Mueller-Joseph LJ, Kopczyk RA. Sanguinaria toothpaste and oral rinse regimen clinical efficacy in short- and long-term trials. J Can Dent Assoc 1990;(7 Suppl):31-3. 3. Frankos VH, Brusick DJ, Johnson EM, Maibach HI, Munro I, Squire RA, et al. Safety of Sanguinaria extract as used in commercial toothpaste and oral rinse products. J Can Dent Assoc 1990;56(7 Suppl)41-7. 4. Hakim SAE. Sanguinarine—a carcinogenic contaminant in Indian edible oils. Indian J Cancer 1968;10:183-97. 5. Schwartz HG. Safety profile of sanguinarine and sanguinaria extract. Compend Contin Educ Dent 1986;Suppl 7:S212-S217. 6. Das M, Khanna SK. Clinicoepidemiological, toxicological, and safety evaluation studies on argemone oil. Crit Rev Toxicol 1997;27:273-97. 7. Sarkar SN. Isolation from argemone oil of dihydrosanguinarine and sanguinarine: toxicity of sanguarine. Nature 1948;162:265-6. 8. Elvin-Lewis M, Lewis WH. New concepts in medical and dental ethanobotany. In: Schultes RE, von Reis S, editors. Ethanobotany: evolution of a discipline. Portland: Cioscorides Press; 1995. p. 303-10. 9. Saran A, Srivastava S, Coutinho E, Maiti M. 1H NMR investigation of the interaction of berberine and sanguinarine with DNA. Indian J Biochem Biophys 1995;32:74-7. 10. Farnsworth NR, Bingel AS, Fong HH, Saleh AA, Christenson GM, Saufferer SM. Oncogenic and tumor-promoting spermatophytes and pteridophytes and their active principles. Cancer Treat Rep 1976;60:1171-214. 11. Upreti KK, Das M, Kumar A, Singh GB, Khanna SK. Biochemical toxicology of argemone oil: short-term oral feeding response in rats. Toxicology 1989;58:285-98. 12. Tandon S, Das M, Khanna SK. Biometabolic elimination and organ retention profile of argemone alkaloid, sanguinarine, in rats and guinea pigs. Drug Metab Dispos 1993;21:194-7. 13. Hakim SAE, Mijovik V, Walker J. Experimental transmission of sanguinarine in milk: detection of a metabolic product. Nature 1961;189:201-4. 14. Maiti M, Nandi R, Chaudhuri K. Interaction of sanguinarine with natural and synthetic deoxyribonucleic acids. Indian J Biochem Biophys 1984;21:158-65. 15. Sen A, Ray A, Maiti M. Thermodynamics of the interaction of sanguinarine with DNA: influence of ionic strength and base composition. Biophys Chem 1996;59:155-70. 16. Weatherell JA, Robinson C, Rathbone MJ. The flow of saliva and its influence on the movement, deposition and removal of drugs administered to the oral cavity. In: Rathbone MJ, editor. Oral mucosal drug delivery. New York: Marcel Dekker; 1996. p. 157-69. 17. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. Philadelphia: WB Saunders; 1995. p. 287. Reprint requests: Douglas D. Damm, DDS Oral & Maxillofacial Pathology UK College of Dentistry 800 Rose Street Lexington, KY 40536-0297
ORAL SURGERY, ORAL MEDICINE, ORAL PATHOLOGY,
ORAL AND MAXILLOFACIAL PATHOLOGY
Editor: Carl M. Allen
Leukoplakia of the maxillary vestibule—an association with Viadent? Douglas D. Damm, DDS,a Alice Curran, DMD, MS,b Dean K. White, DDS, MSD,a and James F. Drummond, MSD, DDS, PhD,a Lexington, Ky, and Jackson, Miss UNIVERSITY OF KENTUCKY AND UNIVERSITY OF MISSISSIPPI
Objective. This report investigates a possible correlation between chronic use of Viadent products and the subsequent development of leukoplakia in the maxillary vestibule.
Study design. A retrospective review of 88 patients with leukoplakia of the maxillary vestibule is presented. Prevalence of Viadent use was determined in this group and in a group of 100 randomly selected adults who presented themselves for routine preadmission screening at a dental school. Results. Of the patients diagnosed with leukoplakia of the maxillary vestibule, 84.1% reported having used Viadent, whereas the prevalence of use was only 3% in the 100 randomly selected adults. Conclusions. Use of Viadent products appears to be associated with an increased prevalence of leukoplakia in the maxillary vestibule.
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:61-6)
The term Viadent refers to brand name formulations of antiplaque toothpaste and oral rinse that use sanguinaria extract, a mixture of benzophenanthridine alkaloids derived from the common bloodroot plant, Sanguinaria canadensis L.1 These oral products, which have shown an antibacterial, antifungal, and anti-inflammatory activity, were introduced in 1982 by Vipont Pharmaceuticals and are currently marketed by Colgate Oral Pharmaceuticals. In April 1990, Vipont organized a symposium in Toronto to review and present research related to the safety and effectiveness of sanguinaria and Viadent products. A thorough review of the previous clinical trials of sanguinaria-containing toothpaste and oral rinses was presented; the review supported a related significant reduction in supragingival plaque, gingival inflammation, and bleeding without adverse mucosal or hard tissue effects.2 A similar thorough evaluation of the toxicity and carcinogenicity was performed, and it aProfessor, Division of Oral & Maxillofacial Pathology, College of Dentistry, University of Kentucky. bAssistant Professor, Department of Diagnostic Sciences, School of Dentistry, University of Mississippi. Received for publication July 2, 1998; returned for revision July 24, 1998; accepted for publication Sept. 2, 1998. Copyright © 1999 by Mosby, Inc. 1079-2104/99/$8.00 + 0 7/14/94688
was concluded that Viadent products exhibit a large margin of safety without any significant danger when they are used as directed in the currently marketed forms of toothpaste and oral rinse.3 Although previous studies 2 decades earlier had suggested a carcinogenic potential,4 the weaknesses in these evaluations were highlighted, and the carcinogenicity was not corroborated on review.3 In addition, the mutagenic potential of sanguinarine was studied in a previous report and found by the Ames test to be negative.5 Although the medical literature often presents a rather clear picture of many controversial topics, information gained from daily patient care also exposes problems previously hidden to the scientific community. This report documents such a discovery.
PATIENT PROFILES Each of 2 patients of a contributing oral surgeon had appeared for treatment with an isolated area of leukoplakia in the maxillary vestibule. Incisional biopsy of the lesions revealed mild epithelial dysplasia. Neither patient used tobacco products or abused alcohol. One of the patients firmly believed that the appearance of her lesion was secondary to her use of Viadent rinse and toothpaste. The second patient was questioned, and she too revealed a positive history of Viadent use. At this point, the surgeon contacted his oral and maxillo61
62 Damm et al
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY January 1999
Fig 1. Discrete leukoplakia of left maxillary facial gingiva that extends onto adjacent alveolar mucosa to depth of vestibule.
Fig 3. Large leukoplakia of anterior maxillary vestibule that extends onto adjacent buccal mucosa. Focal area of erythema on right side represents healing biopsy site.
Fig 2. Focal area of corrugated leukoplakia of right maxillary facial gingiva and alveolar mucosa.
facial pathologist and requested a review of this possible association. Over the next few months, biopsies from several patients who had similar profiles were received; the involved patients also revealed use of Viadent. With the number of newly presented cases enlarging, a search of the last 5 years’ accessions for every biopsy diagnosed as epithelial dysplasia from the maxillary vestibule was performed in an attempt to evaluate previously submitted specimens. Only leukoplakias localized to a discrete zone of the facial maxillary gingiva or the alveolar mucosa between the mucogingival junction and the depth of the vestibule were included (Figs 1, 2, and 3). Extension of the leukoplakia onto the adjacent buccal or labial mucosa was allowed, but patients exhibiting involvement isolated to these 2 locations were excluded. On discovery of the appropriate clinical history, the involved contributor was requested to contact the patient and ask several simple questions; these pertained to prior or present use of Viadent, form and duration of use (if any), and history of tobacco and alcohol consumption.
During this period of time, all new patients appearing for evaluation and treatment of leukoplakias of the maxillary vestibule were questioned in a similar fashion. As a result of a suggestion from representatives of Colgate Oral Pharmaceuticals, the data collection design for newly discovered patients was changed. All future patients were presented with a questionnaire that requested them to identify their current and past oral hygiene products in a list of 12 different toothpastes and 10 different oral rinses, the names of which were arranged in alphabetic order. In addition, the same questionnaire was submitted randomly to 100 patients over 35 years of age who came to the institution of the initiating oral pathologist for routine preadmission screening. An initial group of 80 patients did not use the questionnaire; of these, follow-up could not be obtained from 20. Of the remaining 60 patients, 49 (81.7%) had positive histories of Viadent use. Subsequently, 30 additional patients were identified from newly submitted specimens. To discover the prevelance of Viadent use, this latter group was given the same questionnaire presented to the 100 preadmission patients. Of these 30 patients, 2 did not complete the questionnaire, 3 did not use Viadent, and 25 (89.3%) were positive for Viadent use. Despite the concerns of the Colgate representatives, the questionnaire did not appear to significantly alter the prevalence rate of Viadent use; therefore, the 2 groups have been combined for analysis. With the 2 groups combined, a history of Viadent use was sought from each of a total of 110 patients with leukoplakia of the maxillary vestibule; sufficient followup was obtained from 88 patients. The prevalence of Viadent use in this group is illustrated in Fig 4. The results of the questionnaire randomly administered to the 100 preadmission patients are presented in Fig 5. Of the 3 patients using Viadent, 2 were husband and wife; therefore, the true prevalence could be somewhat lower.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 87, Number 1
Damm et al 63
Fig 4. Prevalence of Viadent use in a group of 88 patients with leukoplakia of maxillary vestibule. Fig 6. Age and gender distribution of patients with leukoplakia of maxillary vestibule and positive history of Viadent use.
Fig 5. Prevalence of Viadent use in a group of 100 patients more than 35 years of age and chosen at random.
All of the patients with histories that were positive for Viadent use were Caucasian; they demonstrated an age range from 38 to 89 years, with a mean age of 60.8 years. The age and gender distribution is presented in Fig 6, with the form of Viadent use illustrated in Fig 7. The duration of use varied from 6 months to 12 years, with a mode of 5 years and a mean of 4.4 years. Fig 8 illustrates the history of tobacco and alcohol use. No tobacco use was noted in 66.2% of the patients. Although 40.9% reported alcohol use, consumption on a regular basis was documented in only 7% of the patients. Histopathologically, the biopsies removed from Viadent users demonstrated remarkable similarity, often allowing the pathologist to predict the history before reviewing the associated patient information. Fig 9 delineates the most commonly noted features, together with the prevalence of these alterations. All cases demonstrated hyperorthokeratosis; mixture with hyperparakeratosis was noted in 11 examples. Seventy-three of the 74 cases demonstrated mild levels of epithelial dysplasia. In 40 of these 73 cases, the dysplastic alterations were minimal (increased cellularity and hyperchromatism of the basilar one third) and represented a borderline level of dysplasia; in 31 of the remaining 33 cases, definitive mild dysplasia was evident, and in 2 cases the dysplasia was moderate in severity. Although mucositis was present almost consistently, the levels were mild in all but 2 cases; in
these 2 cases, the mucositis was moderate in intensity. Although a verruciform surface was present in a significant percentage of cases, the degree of this alteration was minimal in all but 3 cases. In addition to these common findings, melanosis was noted histopathologically in 8 cases and acanthosis in 3 cases. Fig 10 delineates the histopathologic features of a typical lesion. In comparison with adjacent normal mucosa, the affected epithelium is mildly atrophic and exhibits significant hyperorthokeratosis, mild chronic mucositis, and basilar hypercellularity and hyperchromatism. Fig 11 illustrates a similar specimen that is slightly more atrophic and demonstrates mild dysplasia. An example of a lesion with a mildly verruciform surface is presented in Fig 12. Follow-up was obtained from 34 of the patients diagnosed with Viadent-related leukoplakias. In these patients, the duration of follow-up from the date of initial biopsy varied from 8 to 84 months, with a mean of 33.5 months. After the initial biopsy, the lesion was excised completely or ablated with a laser in each of 19 cases; after this procedure, there was complete healing in 13 cases, with no evidence of disease. Six recurrences were seen (31.6%), with 2 ultimately resolving completely over a period of up to 28 months. The lesions in 15 patients received no further therapy after the initial biopsy. In these instances, 4 lesions resolved completely (26.7%), 6 decreased in size (40%), and 5 remained stable (33.3%). In one case, a new lesion arose after resolution of the initial leukoplakia.
DISCUSSION Unfortunately, the method of data collection changed as our study evolved; nevertheless, the association between the presence of leukoplakia in the maxillary vestibule and use of Viadent products is strong and overcomes methodologic arguments. The prevalence of Viadent use in a randomly selected population of adult patients presenting themselves for routine dental care was 3%; this compared with a prevalence of 84.1% of
64 Damm et al
Fig 7. Form of Viadent use in patients affected with leukoplakia of maxillary vestibule.
Fig 8. History of tobacco and alcohol use in patients with leukoplakia of maxillary vestibule and positive history of Viadent use.
patients in the current group affected with leukoplakia of the maxillary vestibule. Despite the thorough review of the literature presented at Vipont’s 1990 symposium in Toronto, a debate still exists with regard to the toxicity and carcinogenicity of sanguinaria. Significant relevant research related to the presence and effects of sanguinaria in certain foodstuffs is ongoing. One such foodstuff is edible oils, which constitute an integral portion of the human diet in many countries, particularly India. The shortage of edible oils prompts unscrupulous traders to adulterate the parent oil with cheaper, nonedible oils. One of these contaminants is argemone oil, which is frequently used because of its easy availability, low cost, and total miscibility with mustard oil, a popular edible oil. Consumption of these contaminated oils may give rise to a number of clinical symptoms that are collectively termed epidemic dropsy. The associated symptoms include vomiting, diarrhea, nausea, swelling of the limbs, erythema, pitting edema, and breathlessness. In severe cases, glaucoma and death secondary to cardiac failure have been reported. As recently as 1997, the toxicity of argemone has been related to its 2 physiologically active benzophenanthridine alkaloids, sanguinarine and dihydrosanguarine.6 With respect to
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY January 1999
Fig 9. Most common histopathologic findings noted in biopsies obtained from patients with leukoplakia of maxillary vestibule and positive history of Viadent use.
these 2 alkaloids, the toxicity of sanguinarine is 2.5 times greater than that of dihydrosanguinarine.7 Scientists who investigate the medical benefits and risks of numerous herbal products in the folk medicine of ethnic groups throughout the world include ethnobotanists and pharmacognosists. Early in the developmental phase of Viadent products, concerns were raised by several of these specialists regarding the safety of the chronic use of sanguinaria extract in dental rinses and toothpastes. It was recognized that health problems related to historic uses for other purposes had been associated with sanguinaria extract and sanguinarine and that potential complications might arise when such highly bioreactive molecules were used on a regular basis and accumulated in the body. In an attempt to address these issues, a number of company-sponsored toxicology studies appeared in the dental literature, and an expert panel was convened to review the results. Even though it was recommended strongly that these results be reported, none of them have appeared in toxicologic journals in which independent verification and careful peer review occur.8 In the company-sponsored review, the only study that was carried out was a 28-day oral mucosal irritancy study conducted in dogs and reported as negative.3 The panel also reviewed 908 case reports provided by consumers after use of Viadent products. In this group, the largest numbers of complaints had to do with burning and stinging in the mouth. It is possible that long-term exposure to an irritant could contribute to the product-associated pathosis documented in the current series. In addition, “weak positive” or “unequivocal” test results of mutagenicity or carcinogenicity were reported, but these were trivialized because of the results of a previous Ames test, which was negative. Inasmuch as the 2 major components of sanguinaria extract, sanguinarine and chelrythrine, are known DNA intercalators, the results of that reported Ames test are drawn into question; frameshift mutants would be expected to
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Fig 10. Typical histopathologic pattern of leukoplakia noted in patients with positive history of Viadent use. Note hyperorthokeratosis, mild epithelial atrophy, mild chronic mucositis, and basilar hypercellularity and hyperchromatism (hematoxylin-eosin, original magnification ×100).
Fig 11. Histopathologic findings of dysplastic leukoplakia of maxillary vestibule removed from patient with positive history of Viadent use. Note hyperorthokeratosis, significant epithelial atrophy, mild epithelial dysplasia, and chronic mucositis (hematoxylin-eosin, original magnification ×400).
be elicited by these types of compounds.9 In the light of accumulating data that continues to fuel this controversy, an “uncertainty factor” regarding safety remains. Although it has been discredited by many investigators (including some who were promoted by Vipont), the early work of Hakim4 on the carcinogenic potential of sanguinaria continues to draw support from several investigators.6,10 In the thorough 1997 review by Das and Khanna,6 sanguinarine and its metabolites were thought likely to be carcinogenic, even in low concentrations, possibly explaining in part the increased prevalence of esophageal and nasopharyngeal cancers in regional portions of the globe.6 Needless to say, agreement on such issues does not exist, and much work still remains incomplete.
Damm et al 65
Fig 12. Histopathologic findings of leukoplakia of maxillary vestibule that was removed from patient with positive history of Viadent use and exhibits mild verruciform surface alteration, hyperorthokeratosis, epithelial atrophy, basilar hyperplasia, and chronic mucositis (hematoxylin-eosin, original magnification ×100).
Are the Viadent-related leukoplakias precancerous? As discussed, uniform agreement on the carcinogenicity of sanguinaria does not exist. The biopsies from 98.6% of the affected patients were graded as dysplastic, but only 2 of these approached a moderate degree of severity, even though approximately 40% of the patients had used the products for more than 5 years. Whether these atypical cellular changes actually represent dysplasia or simply reflect unusual reactive changes is open to question. If the materials are carcinogenic, a long preneoplastic period must exist. If such transformation is possible, it appears that decades of use would be required to document the alteration in a significant number of patients. Why did many of the leukoplakias persist after discontinuation of Viadent or recur after removal and product cessation? Although superficially this may suggest lack of association with Viadent, several important features of the alkaloid must be highlighted. Sanguinarine and its metabolites appear to alter liver metabolism, are eliminated slowly, and are retained in the gastrointestinal tract, liver, lung, kidney, and heart.11,12 Delayed retention in serum is noted and may be due to binding with plasma proteins. 13 Finally, sanguinarine demonstrates the ability to bind to natural host DNA over a wide range of environmental parameters.14,15 Can other oral mucosal sites be affected also? Of the currently reported 74 patients with leukoplakia of the maxillary vestibule, 5 also demonstrated involvement of another site outside the study area. Two of these cases involved the floor of the mouth, 1 the mandibular mucobuccal fold, 1 the buccal mucosa, and 1 the lateral border of the tongue. Because of a high index of suspicion, many clinicians are investigating Viadent use in any patient with leukoplakia and without a history of the typical high risk factors. A small number of
66 Damm et al
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histopathologically similar leukoplakias have been discovered in Viadent users without involvement of the maxillary vestibule. These patients are not included in the present study. Why did the leukoplakias cluster in the maxillary vestibule? This site was not chosen; rather, it was suggested by the surgeon whose patient made the original connection. Since that time, literature that supports the clustering has been produced.16 The perception that saliva quickly dilutes and washes away substances introduced into the mouth is not true. In many cases, such materials adhere to mucosal surfaces, become trapped between teeth, or are retained in sites where the salivary turnover is low. The highly site-specific character of oral mucosal drug delivery has not been appreciated fully by many investigators. When rinses are used, intraoral concentrations are highly variable within different regions, and dramatic differences are revealed. The concentration is noted to be significantly higher in buccal sites than in lingual sites, with the upper sulcus consistently demonstrating a higher concentration than the lower sulcus. These findings are consistent regardless of what material is being used and regardless of the manner in which the substance is introduced to the site (paste or rinse). These differential patterns can persist for hours. Of all oral locations, the anterior portions of the maxillary vestibule have the highest concentration of materials in the mouth; this is due to the distance of the vestibule from all major salivary gland ducts. Only the viscous secretions from minor salivary glands are likely to dilute materials in this area. The concentration in the mandibular vestibule will be less because of rapid dilution from submandibular and sublingual gland secretions. The lowest concentrations occur in the floor of the mouth because of high flow from the sublingual glands and submandibular glands and because of other oral fluids draining into the floor of the mouth. Therefore, as a result of prolonged retention of mouth rinses and toothpastes in the maxillary vestibule, a high prevalence of associated mucosal changes in this area is not surprising. What is appropriate therapy? Initial biopsy is mandatory. Once a histopathologic diagnosis of epithelial dysplasia is obtained, the mucosal pathosis should be treated as any other potentially premalignant process, regardless of its supposed cause, would be treated. As delineated by Neville et al,17 leukoplakia demonstrating moderate epithelial dysplasia or worse warrants eradication. The management of lesions with less severe changes should be guided by individual clinical judgment, according to the size of the lesion, and in light of the response to more conservative measures, such as discontinuation of Viadent use and cessation of any
tobacco use. The vast majority of Viadent-associated leukoplakias manifest minimal levels of dysplasia. In these cases, many clinicians choose close follow-up but no further surgery; however, if significant worsening of the clinical appearance is noted, subsequent surgery with histopathologic evaluation is mandated. REFERENCES 1. Harkrader RJ, Reinhart PC, Rogers JA, Jones RR, Wylie RE II, Lowe BK, et al. The history, chemistry and pharmacokinetics of Sanguinaria extract. J Can Dent Assoc 1990;56(7 Suppl):7-12. 2. Kuftinec MM, Mueller-Joseph LJ, Kopczyk RA. Sanguinaria toothpaste and oral rinse regimen clinical efficacy in short- and long-term trials. J Can Dent Assoc 1990;(7 Suppl):31-3. 3. Frankos VH, Brusick DJ, Johnson EM, Maibach HI, Munro I, Squire RA, et al. Safety of Sanguinaria extract as used in commercial toothpaste and oral rinse products. J Can Dent Assoc 1990;56(7 Suppl)41-7. 4. Hakim SAE. Sanguinarine—a carcinogenic contaminant in Indian edible oils. Indian J Cancer 1968;10:183-97. 5. Schwartz HG. Safety profile of sanguinarine and sanguinaria extract. Compend Contin Educ Dent 1986;Suppl 7:S212-S217. 6. Das M, Khanna SK. Clinicoepidemiological, toxicological, and safety evaluation studies on argemone oil. Crit Rev Toxicol 1997;27:273-97. 7. Sarkar SN. Isolation from argemone oil of dihydrosanguinarine and sanguinarine: toxicity of sanguarine. Nature 1948;162:265-6. 8. Elvin-Lewis M, Lewis WH. New concepts in medical and dental ethanobotany. In: Schultes RE, von Reis S, editors. Ethanobotany: evolution of a discipline. Portland: Cioscorides Press; 1995. p. 303-10. 9. Saran A, Srivastava S, Coutinho E, Maiti M. 1H NMR investigation of the interaction of berberine and sanguinarine with DNA. Indian J Biochem Biophys 1995;32:74-7. 10. Farnsworth NR, Bingel AS, Fong HH, Saleh AA, Christenson GM, Saufferer SM. Oncogenic and tumor-promoting spermatophytes and pteridophytes and their active principles. Cancer Treat Rep 1976;60:1171-214. 11. Upreti KK, Das M, Kumar A, Singh GB, Khanna SK. Biochemical toxicology of argemone oil: short-term oral feeding response in rats. Toxicology 1989;58:285-98. 12. Tandon S, Das M, Khanna SK. Biometabolic elimination and organ retention profile of argemone alkaloid, sanguinarine, in rats and guinea pigs. Drug Metab Dispos 1993;21:194-7. 13. Hakim SAE, Mijovik V, Walker J. Experimental transmission of sanguinarine in milk: detection of a metabolic product. Nature 1961;189:201-4. 14. Maiti M, Nandi R, Chaudhuri K. Interaction of sanguinarine with natural and synthetic deoxyribonucleic acids. Indian J Biochem Biophys 1984;21:158-65. 15. Sen A, Ray A, Maiti M. Thermodynamics of the interaction of sanguinarine with DNA: influence of ionic strength and base composition. Biophys Chem 1996;59:155-70. 16. Weatherell JA, Robinson C, Rathbone MJ. The flow of saliva and its influence on the movement, deposition and removal of drugs administered to the oral cavity. In: Rathbone MJ, editor. Oral mucosal drug delivery. New York: Marcel Dekker; 1996. p. 157-69. 17. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. Philadelphia: WB Saunders; 1995. p. 287. Reprint requests: Douglas D. Damm, DDS Oral & Maxillofacial Pathology UK College of Dentistry 800 Rose Street Lexington, KY 40536-0297