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Tobacco use and cancer
Vol. 80 No. 2 August 1995
ORAL A N D MAXILLOFACIAL PATHOLOGY
Tobacco
Editor." Carl M. Allen
use and cancer
A reappraisal N a d a r a j a h V i g n e s w a r a n , D r M e d Dent, a K e n Tilashalski, D M D , b B r a d Rodu, D D S , a and Philip Cole, M D , D r P H , c B i r m i n g h a m , Ala. SCHOOL OF DENTISTRY AND SCHOOL OF PUBLIC HEALTH, UNIVERSITY OF ALABAMA AT BIRMINGHAM
With approximately six million users, smokeless tobacco has received considerable scrutiny as a risk factor for oral cancer. We review the relationship between smokeless tobacco use, keratosis, and oral cancer. Several features of smokeless tobacco keratosis, including the natural history, clinical presentation, and biologic behavior, differentiate it from other leukoplakias that exhibit greater malignant potential. Previous research has demonstrated that the relative risk of oral cancer with smokeless tobacco use is 4.2, about half of the risk from smoking (relative risk = 10 to 15). Mortality data from populations with sustained high-frequency smokeless tobacco use do not support the mistaken prediction of an epidemic of oral cancer with increasing smokeless tobacco use. In fact, the risks of smokeless tobacco use compare so favorably with those of smoking that smokers who switch to smokeless tobacco reduce their risks for all tobacco-related illnesses including oral cancer. Although some criticize this proposal as less than an ideal solution for the nation's smokers, full adoption of this strategy would eventually save over 400,000 lives each year. (ORAL SURGORAL MED ORAL PATHOL ORAL RADIOL ENDOD 1995;80:178-82)
O r a l cancer is one o f the 10 m o s t frequent cancers w o r l d w i d e . In the U n i t e d States it accounts for a p p r o x i m a t e l y 4 % o f cancers in m e n and 2% in w o m e n , 1 and the A m e r i c a n C a n c e r Society estimates that about 30,000 n e w cases will be d i a g n o s e d in 1995. 2 The p r e d o m i n a n t causes o f oral cancer in the U.S. and other d e v e l o p e d countries are s m o k i n g and a l c o h o l consumption. 3, 4 B e c a u s e there are an e s t i m a t e d six m i l l i o n users in the U n i t e d States, s m o k e l e s s t o b a c c o (ST) has also r e c e i v e d c o n s i d e r a b l e scrutiny as a cause o f oral cancer. 5 S T has attracted attention for several additional reasons. First, the m e d i a has g i v e n attention to p r o m inent users, e s p e c i a l l y m a j o r league b a s e b a l l p l a y ers. 6-8 Public health p r o f e s s i o n a l s are c o n c e r n e d that aDepartment of Oral Pathology, School of Dentistry. bDepartment of Oral Diagnosis, School of Dentistry. CDepartment of Epidemiology, School of Public Health. Received for publication Aug. 7, 1994; revision requested Sept. 10, 1994; accepted for publication Oct. 19, 1994. Copyright 9 1995 by Mosby-Year Book, Inc. 1079-2104/95/$3.00 + 0 7/14/61501
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these athletes serve as role m o d e l s for a d o l e s c e n t initiation into S T use. Second, ST use frequently leads to the d e v e l o p m e n t o f keratosis, 9, 10 w h i c h is a s s u m e d to i m p a r t h i g h oral c a n c e r risk. u, 12 Third, a high incidence o f oral cancer has been related to ST use in part b e c a u s e o f the e x p e r i e n c e in the I n d i a n subcontinent. 13 A l t h o u g h various factors p r e c l u d e direct application to the A m e r i c a n experience, 14 the Indian oral cancer rates have b e e n cited as p r e d i c t i v e o f future trends in the U n i t e d States if S T use increases.15, 16 F i n a l l y , oral c a n c e r has been o b s e r v e d in elderly S T users in the U n i t e d States. 17, 18 One o f us (B.R.) has recently p r o p o s e d that ST be c o n s i d e r e d as an alternative nicotine source for smokers w h o are unable or unwilling to quit tobacco entirely. 19 T h e p r o p o s a l has been criticized b e c a u s e S T use is a risk factor for oral cancer. S o m e persons have p r e d i c t e d that i n c r e a s e d ST use will l e a d to an " e p i d e m i c " o f oral cancer, z~ This article reviews the e v i d e n c e for this prediction, with special emphasis on s m o k e l e s s t o b a c c o keratosis (STK), a form o f l e u k o p l a k i a . W e c o m p a r e the risks o f ST use with
ORAL SURGERY ORAL MEDICINEORAL PATHOLOGY Volume 80, Number 2 those of smoking and discuss other facets of this proposal.
ST USE A N D LEUKOPLAKIA Oral leukoplakia was originally defined in 1978 by the World Health Organization as a "white patch or plaque that cannot be characterized clinically or pathologically as any other disease. ''21 This definition was recognized as overly broad, and in 1984 a revised definition excluded white lesions such as frictional keratoses and also specified tobacco-induced leukoplakias as a distinct category. 22 Furthermore, STK was separated from smoking-related leukoplakia on the basis of presentation with additional differences in prevalence, frequency of dysplasia, and rate of malignant transformation. 22, 23 STK is common; it occurs in up to 60% of ST users. 9"12 The frequency of its appearance is dependent on the type of ST used. Moist snuff, which is more alkaline than chewing tobacco, more often leads to STK. 12However, moist snuff in preportioned pouches causes less pronounced mucosal changes and fewer cases of STK than does the loose form. 24 STK arises at the site of ST use usually within 6 months to 3 years of initiation. 12, 25 The epithelial changes largely are a response to local irritation. 25' 26 Oral leukoplakia occurs in less than 1% of the general population, primarily in long-time smokers 40 to 60 years old. 27, 28 Whereas STK occurs only at the site of ST placement, smoking places the mucosa of the entire airway at risk. Smoking-related leukoplakias most commonly involve the floor of mouth, ventral tongue, and soft palate. Not coincidentally, these sites account for 75% of oral cancer in the United States. 27, 29 Oral cancer is often preceded by changes in the mucosal epithelium that are collectively referred to as dysplasia. Mild dysplasia involves only the basal or deeper levels of the epithelium. As the dyspiasia involves a greater proportion of the epithelium (that is, moderate to severe), the development of invasive cancer becomes more likely. A retrospective study from the United States reported that about 20% of 3360 cases of oral leukoplakia showed some degree of dysplasia. 3~ In contrast, dysplasia is seen in less than 3% of cases of STK. 3a-34 Even when dysplasia is present in STK, it is usually found in earlier stages than in oral leukoplakia. 35, 36 With the prevalence and degree of dysplasia low, it is not surprising that malignant transformation occurred in only 0 to 1.2% of cases of STK over 5 years. 37-38 One prospective study found no case of cancer in 1550 persons with STK followed for 10
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years. 37 Another study reported no case of oral cancer among 500 regular ST users followed for 6 years. 38 This low rate of malignant transformation has also been found experimentally in animals. 39, 40 In comparison, as many as 17% of oral leukoplakias will transform to carcinoma within 7 years. 41
ST USE A N D ORAL CANCER During the past decade warnings with respect to the risks of ST use have focused on oral cancer. Examination of research from around the world reveals the magnitude of this risk. Oral cancer is one of the most common cancers in India. 42 Although ST use is often cited as a major determinant of this high incidence, there are other contributing factors. First, processing of ST in India is done by individual farmers and small companies with little control over fermentation and curing. This increases the production of potentially carcinogenic nitrosamines. 43 Improvements in tobacco agriculture and ST processing in the United States have resulted in a substantial decline in the concentration of several of the more important carcinogens. 44 Second, in India the composition and usage of ST is not homogeneous but differs considerably from region to region. 14 For example, ST is often combined with other agents including betel leaf (Piper betle), sliced areca nut (Areca catechu), and powdered slaked lime. 14 These additives, used to enhance the psychotropic effects of nicotine, make the combination more genotoxic than tobacco alone. 45,46 Third, Indian ST users often smoke concurrently, thus confounding the effects of ST use. 13' 47 Other populations with sustained high frequency of ST use are of interest. In West Virginia, almost one quarter of white men use ST, 48 a pattern that has existed for many decades. This compares with a national ST usage rate of 6%. 48 Nonetheless, the oral cancer mortality rate in men in West Virginia during the period of 1950 to 1980 remained stable at 3.0 to 3.2 deaths per 100,000 person-years and below the national average of 4.2 to 4.5. 49 Sweden has been the world's largest per capita consumer of ST throughout the 20th century 5~ without a resultant oral cancer epidemic. 51 On the contrary, the age-adjusted mortality rate for oral cancer from 1960 to 1990 in Sweden was low and remarkably stable at 2.3 to 3.6 per 100,000 person-years. 51 A retrospective study of 200,000 male snuff dippers in Sweden found only one case of oral cancer per year. 52 This is in marked contrast to most other European countries where ST use is essentially nonexistent and where increases in oral cancer mortality
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have mirrored earlier increases in cigarette consumption.4, 51 The greatest increase in oral cancer mortality has occurred in France (13.4/100,000 person-years in 1955-59 to 32.3/100,000 person-years in 1985-89.) 4, 51 It is not surprising to find that Swedish lung cancer mortality rates have been the lowest in Europe over the past 40 years. 53 These large scale vital statistics from Sweden and France strongly support the suggestion that if tobacco is to be used, it should be in the form of ST and not cigarettes. The population that uses ST in lieu of smoking is, in effect, protected from lung cancer and other major smoking-related diseases and suffers little or no increased risk of oral cancer.
DISCUSSION A recent proposal has recommended ST use as an alternative for adult smokers who are unable or unwilling to stop smoking. 19 Crucial to this proposal is the realization that ST use carries a lower risk of oral cancer than does continued smoking and has virtually no other consequential adverse effects. In fact, the annual incidence rate of oral cancer among American ST users has been estimated at 26 cases per 100,000 person-years. This is a relative risk of 4.2 compared with nonusers of tobacco. 18 If the nation's current 46 million smokers instead used ST, then 12,000 new cases of oral cancer would occur annually, 19 based on an incidence rate of STinduced oral cancer of 26 cases per 100,000 long-term users. 18 These 12,000 cases represent less than 5% of all smoking-related cancers, less than 10% of smoking-related lung cancers, and less than 50% of the 27,000 cases of oral cancers now attributed to smoking each year. Thus the substitution of ST for cigarettes would result in a substantial reduction in all tobacco-related health effects, including oral cancer. Although oral cancer has about a 50% mortality rate, the 6,000 deaths that would result pales in comparison with the number of people who die each year from the health consequences of smoking. Currently, 419,000 Americans die yearly from smoking-related illnesses including cardiovascular disease (180,000), cancer (148,000), and respiratory disease (85,000). 54 A recent analysis of American data confirms that the impact of ST use on life expectancy is minimal. 55 The study revealed that both ST users and nontobacco users have an average life expectancy that is 8 years longer than cigarette smokers. In one of the largest series of oral cancer cases related to ST use, the average age at diagnosis was 78 years (as opposed to an average age of 60 years for smoking-related head and neck cancer) 3, 29 and followed an average of 55 years of ST use. 56
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY August 1995 Some critics charge that a switch from smoking to ST use is a trade of body parts, lung cancer for oral cancer. There is no trade; about 90% of the oral cancer cases seen in the United States are attributable to smoking 57 and only about 5% are related to ST use. By direct comparison, the relative risk (RR) of oral cancer from ST use (RR = 4.2) 18 is about half that of the risk from smoking (RR = 10 to 15). 58 The RR of oral cancer with ST use is often misrepresented. For example, a frequent comment is " S T users are 50 times more likely to develop oral cancer than abstainers."59 This high RR estimate pertains only to gingival cancer, a rare form of oral cancer, and only after more than 50 years of use. 18 When examining a rare phenomenon, such as gingival cancer, small changes in the number of cases, or even chance, will produce highly variable risk estimates. This is exemplified by the fact that the 95% confidence interval for the 50-fold increased risk extends from 9 to 250.18 Recommending a switch from cigarette smoking to ST has also elicited ethical concerns. 6~ 61 In considering these concerns it is important to remember that recommendations from health professionals almost always involve a tradeoff of risks and benefits. For example, radiation and chemotherapy are standard cancer treatment options even though they cause disease, some as severe as a second malignancy. The same principle applies to strategies in preventive medicine. Tamoxifen, an estrogen antagonist, is under study by the National Cancer Institute as a prophylactic measure for primary breast cancer in highrisk women. 62 Although tamoxifen may reduce the risk of breast cancer, it increases the risk of uterine cancer 7.5-fold. 62 However, the National Cancer Institute considers the risk/benefit balance favorable enough to justify the study. 62 A switch to ST use for inveterate smokers can be similarly justified--if not ethically mandated. Full adoption of this strategy would eventually save over 400,000 lives each year, a 98% reduction in deaths from all tobacco-related illnesses. This proposal is not an invitation to nonusers of tobacco to start; it is intended solely as a risk reduction strategy for the current smoker. The message is directed at adult smokers as an alternative to conventional cessation programs and nicotine substitution. Sadly, current smoking cessation programs end in failure for over 75% of smokers who try them. Although all tobacco use carries some risk, a reduction in risks for these inveterate smokers by a switch to ST will save lives. With one in five Americans dying from smoking-related illnesses, it is imperative to implement any strategy that can significantly reduce mortality.
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Volume 80, Number 2 REFERENCES 1, Parkin DM, Laara E, Muir CS. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 1988; 41:184-97. 2, Boring CC, Squires TS, Tong T. Cancer statistics, 1994. CA Cancer J Clin 1994;44:7-26. 3. Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988;48:3282-7. 4. Hill C, Benhamou E, Doyan F. Trends in cancer mortality, France 1951-1985. Br J Cancer 1991;63:587-90. 5. Centers for Disease Control and Prevention. Use of smokeless tobacco among adults, United States 1991. MMWR Morb Mortal Wldy Rep 1993;42:263-6. 6. Connolly GN, Orleans CT, Kogan M. Use of smokeless tobacco in major league baseball. N Engl J Med 1988;318:1281-5. 7. Connolly GN, Orleans CT. Snuffing tobacco out of sport. Am J Public Health 1992;82:351'3. 8. Pro sports and smokeless tobacco. Am Fam Physician 1987; 35:97. 9. Poulson TC, Lindenmuth JE, Greer RO Jr. A comparison of the use of smokeless tobacco in rural and urban teenagers: CA Cancer J Clin 1984;34:248-61. 10. Grady D, Greene J, Daniels TE, et al. Oral mucosal lesions found in smokeless tobacco users. J Am Dent Assoc 1990; 121:117-23. 11. Sinusas K, Coroso JG, Sopher MD, Carbtree BF. Smokeless tobacco use and oral pathology in a professional baseball organization. J Fam Pract 1992;34:713-8. 12. Greene JC, Ernster VL, Grady DG, Robertson PB, Walsh MM, Stillman LA. Oral mucosal lesions: clinical findings in relation to smokeless tobacco use among U.S. baseball players. monograph 2. Smokeless tobacco or health: an intemational perspective. NIH publication No. 93-3461:41-50, 1993. 13. Hirayama T. An epidemiological study of oral and pharyngeal cancer in Central and South-East Asia. Bull World Health Organ 1966;34:41-69. 14. Muir CS, Zaridze DG. Smokeless tobacco and cancer: an overview. Lyon, France: International Agency for Research on Cancer Scientific Publications, 1986;74:35-44. 15. AMA Council on Scientific Affairs. Health effects of smokeless tobacco. JAMA 1986;255:1038-44. 16. Squier CA. Smokeless tobacco and oral cancer: A cause for concern? CA Cancer J Clin 1984;34:242-7. 17. Peacock EE Jr, Greenberg BG, Brawley BW. The effect of snuff and tobacco on the production of oral carcinoma: an experimental and epidemiological study. Ann Surg 1960; 151: 542-50. 18. Winn DM, Blot WJ, Shy CM, Pickle LW, Toledo A, Fraumeni JF. Snuff dipping and oral cancer among women in the southern United States. N Engl J Med 1981;304:745-9. 19. Rodu B. An alternative approach to smoking control. Am J Med Sci 1994;308:32-4. 20. Palmer C. Dr. Novello targets smokeless. ADA News. January 4, 1993:16. 21. World Health Organization. Definition ofleukoplakiaandrelated lesions: an aid to studies on oral precancer. ORAL SURG ORAL MED ORAL PATHOL 1978;46:518-39. 22. Axell T, Holmstrup P, Kramer IRH, Pindborg JJ, Shear M. International seminar on oral leukoplakias and associated lesions related to tobacco habits. Community Dent Oral Epidemiol 1984;12:145-54. 23. Bouquot JE. Reviewing oral leukoplakia: clinical concepts for the 1990s. J Am Dent Assoc 1991;122:80-2. 24. Anderson G, Axell T. Clinical appearance of lesions associated with the use of loose and portion-bag packed Swedish moist snuff: a comparative study. J Oral Pathol Med 1989; 18:2-7. 25. Greer RO, Poulson TC. Oral tissue alteration associated with the use of smokeless tobacco by teen agers: Part 1. clinical findings. OVALSta~GORALMED ORALPATHOL1983;56:275-84. 26. Greer RO, Poulson TC, Boone ME, Lindenmuth JE, Crosby
27.
28.
29. 30. 31.
32. 33. 34. 35.
36. 37. 38.
39. 40. 41.
42. 43. 44.
45.
46. 47.
48.
L. Smokeless tobacco associated oral changes in juvenile, adult, and geriatic patients: clinical and histomorphologic features. Gerodontics 1986;2:87-98. Bouquot JE, Weiland L, Ballard D, Kurland L. Leukoplakia of the mouth and pharynx in Rochester, Minnesota, 19351984: incidence, clinical features, and follow-up of 463 patients from a relatively unbiased patient pool. J Oral Pathol 1988; 17:436. Bouquot JE, Gorlin RJ. Leukoplalda, lichen planus, and other oral keratoses in 23,616 white Americans over the age of 35 years. ORALSURGORALMEt) ORALPATHOL 1986;61:37381. Silverman S, Gorsky M. Epidemiologic and demographic update in oral cancer: California and national data 1973 to 1985. J Am Dent Assoc 1990;120:495-9. Waldron CA, Shaffer G. Leukoplakia revisited: a clinicopathologic study 3256 of oral leukoplakias. Cancer 1975;36: 1386-92. Bouquot J, Schhhroeder K. Oral leukoplakia and smokeless tobacco keratoses are two separate and distinctive precancers. ORAL SURG ORAL MED ORAL PATHOL 1993;76:588-9. Smith JF, Mincer HA, Hopkins KP, Bell J. Snuff-dipper's lesion: a cytological and pathological study in a large population. Arch Otolaryngol 1970;92:450-6. Roed-Petersen B, Pindborg JJ. A study of snuff-induced oral leukoplakias. J Oral Pathol 1973;2:301-13. Axell T, Momstad H, Sundstrom B. The relation of the clinical picture to the histopathology of snuff dipper's lesions in a Swedish population. J Oral Pathol 1976;5:229-36. Mincer HH, Coleman SA, Hopkins KP. Observations on the clinical characteristics of oral lesions showing histologic epithelial dysplasia. ORALSUR6 ORALMED ORALPATHOL 1972; 33:389-99. Kaugars GE, MehailescU WL, Gunsolley JC. Smokeless tobacco use and oral epithelial dysplasia. Cancer 1989;64:152730. Smith JF. Snuff-dippers' lesions: a ten-year follow-up. Arch Otolaryngol 1975;101:276-7. Christen AG, McDonald JL, Christen JA. The impact of tobacco use and cessation on nonmaligant and precancerous oral and dental diseases and condition. Indianapolis: Indiana University School of Dentistry teaching monograph. Precancerous condition. June 1991:7-13. Chen SY. Effects of smokeless tobacco on the buccal mucosa of HMT rats. J Oral Pathol Med 1989;18:108-12. Park NH, Sapp JP, Herbosa EG. Oral cancer induced in hamsters with herpes simplex infection and stimulated snuff dipping. ORAL SURG ORAL MED ORAL PATHOL 1986;62:164-8. Silverman S, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation: a follow-up study of 257 patients. Cancer 1984;36:563-8. Sankaranarayanan R, Nair MK, Mathew B, Balaram P, Sebastian P, Chandra Dutt S. Recent results of oral cancer research in Kerala, India. Head Neck 1992;14:107-12. Brunnemann KD, Genoble L, Hoffmann D. N-Nitrosamines in chewing tobacco: an international comparison. J Agric Food Chem 1985;33:1178-81. Brnnnemann KD, Hoffmann D. Chemical composition of smokeless tobacco products. Monograph 2. Smokeless tobacco or health: an international perspective. NIH publication No: 93-3461:96-105, 1993. Wary KK, Sharan RW. Aqueous extract of betel nut of northeast India induces DNA-strand breaks and enhances rate of cell proliferation in vitro: effects of betel-nut extract in vitro. J Cancer Res Clin Oncol 1988;114:579-82. Thomas SJ, MacLennan R. Slaked lime and betal nut cancer in Papua, New Guinea. Lancet 1992;340:577-8. Jayant K, Balakrishhhnan V, Sanghvi LD, Jussawalla DJ. Quantification of the role of smoking and chewing tobacco in oral, pharyngeal, and oesophageal cancers. Br J Cancer 1977; 35:232-4. Marcus AC, Crane LA, Shopland DR, Lynn WR. Use of
182
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49.
50. 51. 52. 53.
54. 55. 56.
57.
58.
smokeless tobacco in the United States: recent estimates from the current population survey. NCI monograph 1989;8: 17-23. Mason TJ, McKay FW. US Cancer mortality by county: 1950-1969. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, DHEW Publication No. (NIH) 74-615, 1974. Nordgren P, Ramstrom L. Moist snuff in Sweden: tradition and evolution. Br J Addict 1990;85:1107-12. La Vecchia C, Lucchini F, Negri E, Boyle P, Malsonneuve P, Levi F. Trends of cancer mortality in Europe, 1955-1989: I. digestive sites. Eur J Cancer 1992;28:132-235. Axell T, Mornstad H, Sundstrom B. Snuff and cancer of the oral cavity: a retrospective study. Lakartidningen 1978;75: 1224-6. La Vecchia C, Lucchini F, Negri E, Boyle P, Maisonneuve P, Levi F. Trends of cancer mortality in Europe, 1955-1989: II. respiratory tract, bone, connective and soft tissue sarcomas, and skin. Eur J Cancer 1992;28:514-99. Centers for Disease Control. Cigarette smoking-attributable mortality and years of potential life lost: United States, 1990. MMWR Morb Mortal Wkiy Rep 1993;42:645-9. Rodu B, Cole P, Tobacco-related mortality. Nature 1994; 370:184. McGuitt WF, Wray A. Oral carcinoma and smokeless tobacco use: a clinical profile. Monograph 2. Smokeless tobacco or health: an international perspective. NIH publication No. 933461:91-5, 1993. US Department Of Health and Human Services. The health consequences of smoking: 25 years of progress. A report of the Surgeon General, U.S. Department of Health and Human Services. Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. DHHS Publication No. (CDC) 89-8416:1990. Stockwell HG, Lyman GH. Impact of smoking and smokeless
59. 60. 61. 62.
tobacco on the risk of cancer of the head and neck. Head Neck Surg 1986;9:104-10. Blowing smoke at Congress. New York Times. April 17, 1994. Nelson C. University of Alabama smokeless tobacco study under fire. JNCI 1994;86:1193, Jacob JA. Smokeless advice 'irresponsible'. ADA News, October 3, 1994. Taylor R. Trials and errors in breast-cancer research. J NIH Res 1994;6:27-30.
Reprint requests: Brad Rodu, DDS SDB 81 UAB Birmingham, AL 35294-0007
Editor's Note: We realize that the material presented by Dr. Vigneswaran and colleagues represents an area of biomedical science that has the potential to elicit strong emotions. Science should not be based solely on emotion, however, and these investigators have examined the problem of tobacco use and carcinogenesis from a perspective that may seem foreign to many of our readers. Nevertheless, in the spirit of scientific inquiry', we invite the readership to comment on the concepts proposed in this article. Selected letters will be published together with the authors' responses in a future issue.
Carl M. Allen, DDS, MSD Oral and Maxillofacial Pathology Section
ORAL A N D MAXILLOFACIAL PATHOLOGY
Tobacco
Editor." Carl M. Allen
use and cancer
A reappraisal N a d a r a j a h V i g n e s w a r a n , D r M e d Dent, a K e n Tilashalski, D M D , b B r a d Rodu, D D S , a and Philip Cole, M D , D r P H , c B i r m i n g h a m , Ala. SCHOOL OF DENTISTRY AND SCHOOL OF PUBLIC HEALTH, UNIVERSITY OF ALABAMA AT BIRMINGHAM
With approximately six million users, smokeless tobacco has received considerable scrutiny as a risk factor for oral cancer. We review the relationship between smokeless tobacco use, keratosis, and oral cancer. Several features of smokeless tobacco keratosis, including the natural history, clinical presentation, and biologic behavior, differentiate it from other leukoplakias that exhibit greater malignant potential. Previous research has demonstrated that the relative risk of oral cancer with smokeless tobacco use is 4.2, about half of the risk from smoking (relative risk = 10 to 15). Mortality data from populations with sustained high-frequency smokeless tobacco use do not support the mistaken prediction of an epidemic of oral cancer with increasing smokeless tobacco use. In fact, the risks of smokeless tobacco use compare so favorably with those of smoking that smokers who switch to smokeless tobacco reduce their risks for all tobacco-related illnesses including oral cancer. Although some criticize this proposal as less than an ideal solution for the nation's smokers, full adoption of this strategy would eventually save over 400,000 lives each year. (ORAL SURGORAL MED ORAL PATHOL ORAL RADIOL ENDOD 1995;80:178-82)
O r a l cancer is one o f the 10 m o s t frequent cancers w o r l d w i d e . In the U n i t e d States it accounts for a p p r o x i m a t e l y 4 % o f cancers in m e n and 2% in w o m e n , 1 and the A m e r i c a n C a n c e r Society estimates that about 30,000 n e w cases will be d i a g n o s e d in 1995. 2 The p r e d o m i n a n t causes o f oral cancer in the U.S. and other d e v e l o p e d countries are s m o k i n g and a l c o h o l consumption. 3, 4 B e c a u s e there are an e s t i m a t e d six m i l l i o n users in the U n i t e d States, s m o k e l e s s t o b a c c o (ST) has also r e c e i v e d c o n s i d e r a b l e scrutiny as a cause o f oral cancer. 5 S T has attracted attention for several additional reasons. First, the m e d i a has g i v e n attention to p r o m inent users, e s p e c i a l l y m a j o r league b a s e b a l l p l a y ers. 6-8 Public health p r o f e s s i o n a l s are c o n c e r n e d that aDepartment of Oral Pathology, School of Dentistry. bDepartment of Oral Diagnosis, School of Dentistry. CDepartment of Epidemiology, School of Public Health. Received for publication Aug. 7, 1994; revision requested Sept. 10, 1994; accepted for publication Oct. 19, 1994. Copyright 9 1995 by Mosby-Year Book, Inc. 1079-2104/95/$3.00 + 0 7/14/61501
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these athletes serve as role m o d e l s for a d o l e s c e n t initiation into S T use. Second, ST use frequently leads to the d e v e l o p m e n t o f keratosis, 9, 10 w h i c h is a s s u m e d to i m p a r t h i g h oral c a n c e r risk. u, 12 Third, a high incidence o f oral cancer has been related to ST use in part b e c a u s e o f the e x p e r i e n c e in the I n d i a n subcontinent. 13 A l t h o u g h various factors p r e c l u d e direct application to the A m e r i c a n experience, 14 the Indian oral cancer rates have b e e n cited as p r e d i c t i v e o f future trends in the U n i t e d States if S T use increases.15, 16 F i n a l l y , oral c a n c e r has been o b s e r v e d in elderly S T users in the U n i t e d States. 17, 18 One o f us (B.R.) has recently p r o p o s e d that ST be c o n s i d e r e d as an alternative nicotine source for smokers w h o are unable or unwilling to quit tobacco entirely. 19 T h e p r o p o s a l has been criticized b e c a u s e S T use is a risk factor for oral cancer. S o m e persons have p r e d i c t e d that i n c r e a s e d ST use will l e a d to an " e p i d e m i c " o f oral cancer, z~ This article reviews the e v i d e n c e for this prediction, with special emphasis on s m o k e l e s s t o b a c c o keratosis (STK), a form o f l e u k o p l a k i a . W e c o m p a r e the risks o f ST use with
ORAL SURGERY ORAL MEDICINEORAL PATHOLOGY Volume 80, Number 2 those of smoking and discuss other facets of this proposal.
ST USE A N D LEUKOPLAKIA Oral leukoplakia was originally defined in 1978 by the World Health Organization as a "white patch or plaque that cannot be characterized clinically or pathologically as any other disease. ''21 This definition was recognized as overly broad, and in 1984 a revised definition excluded white lesions such as frictional keratoses and also specified tobacco-induced leukoplakias as a distinct category. 22 Furthermore, STK was separated from smoking-related leukoplakia on the basis of presentation with additional differences in prevalence, frequency of dysplasia, and rate of malignant transformation. 22, 23 STK is common; it occurs in up to 60% of ST users. 9"12 The frequency of its appearance is dependent on the type of ST used. Moist snuff, which is more alkaline than chewing tobacco, more often leads to STK. 12However, moist snuff in preportioned pouches causes less pronounced mucosal changes and fewer cases of STK than does the loose form. 24 STK arises at the site of ST use usually within 6 months to 3 years of initiation. 12, 25 The epithelial changes largely are a response to local irritation. 25' 26 Oral leukoplakia occurs in less than 1% of the general population, primarily in long-time smokers 40 to 60 years old. 27, 28 Whereas STK occurs only at the site of ST placement, smoking places the mucosa of the entire airway at risk. Smoking-related leukoplakias most commonly involve the floor of mouth, ventral tongue, and soft palate. Not coincidentally, these sites account for 75% of oral cancer in the United States. 27, 29 Oral cancer is often preceded by changes in the mucosal epithelium that are collectively referred to as dysplasia. Mild dysplasia involves only the basal or deeper levels of the epithelium. As the dyspiasia involves a greater proportion of the epithelium (that is, moderate to severe), the development of invasive cancer becomes more likely. A retrospective study from the United States reported that about 20% of 3360 cases of oral leukoplakia showed some degree of dysplasia. 3~ In contrast, dysplasia is seen in less than 3% of cases of STK. 3a-34 Even when dysplasia is present in STK, it is usually found in earlier stages than in oral leukoplakia. 35, 36 With the prevalence and degree of dysplasia low, it is not surprising that malignant transformation occurred in only 0 to 1.2% of cases of STK over 5 years. 37-38 One prospective study found no case of cancer in 1550 persons with STK followed for 10
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years. 37 Another study reported no case of oral cancer among 500 regular ST users followed for 6 years. 38 This low rate of malignant transformation has also been found experimentally in animals. 39, 40 In comparison, as many as 17% of oral leukoplakias will transform to carcinoma within 7 years. 41
ST USE A N D ORAL CANCER During the past decade warnings with respect to the risks of ST use have focused on oral cancer. Examination of research from around the world reveals the magnitude of this risk. Oral cancer is one of the most common cancers in India. 42 Although ST use is often cited as a major determinant of this high incidence, there are other contributing factors. First, processing of ST in India is done by individual farmers and small companies with little control over fermentation and curing. This increases the production of potentially carcinogenic nitrosamines. 43 Improvements in tobacco agriculture and ST processing in the United States have resulted in a substantial decline in the concentration of several of the more important carcinogens. 44 Second, in India the composition and usage of ST is not homogeneous but differs considerably from region to region. 14 For example, ST is often combined with other agents including betel leaf (Piper betle), sliced areca nut (Areca catechu), and powdered slaked lime. 14 These additives, used to enhance the psychotropic effects of nicotine, make the combination more genotoxic than tobacco alone. 45,46 Third, Indian ST users often smoke concurrently, thus confounding the effects of ST use. 13' 47 Other populations with sustained high frequency of ST use are of interest. In West Virginia, almost one quarter of white men use ST, 48 a pattern that has existed for many decades. This compares with a national ST usage rate of 6%. 48 Nonetheless, the oral cancer mortality rate in men in West Virginia during the period of 1950 to 1980 remained stable at 3.0 to 3.2 deaths per 100,000 person-years and below the national average of 4.2 to 4.5. 49 Sweden has been the world's largest per capita consumer of ST throughout the 20th century 5~ without a resultant oral cancer epidemic. 51 On the contrary, the age-adjusted mortality rate for oral cancer from 1960 to 1990 in Sweden was low and remarkably stable at 2.3 to 3.6 per 100,000 person-years. 51 A retrospective study of 200,000 male snuff dippers in Sweden found only one case of oral cancer per year. 52 This is in marked contrast to most other European countries where ST use is essentially nonexistent and where increases in oral cancer mortality
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have mirrored earlier increases in cigarette consumption.4, 51 The greatest increase in oral cancer mortality has occurred in France (13.4/100,000 person-years in 1955-59 to 32.3/100,000 person-years in 1985-89.) 4, 51 It is not surprising to find that Swedish lung cancer mortality rates have been the lowest in Europe over the past 40 years. 53 These large scale vital statistics from Sweden and France strongly support the suggestion that if tobacco is to be used, it should be in the form of ST and not cigarettes. The population that uses ST in lieu of smoking is, in effect, protected from lung cancer and other major smoking-related diseases and suffers little or no increased risk of oral cancer.
DISCUSSION A recent proposal has recommended ST use as an alternative for adult smokers who are unable or unwilling to stop smoking. 19 Crucial to this proposal is the realization that ST use carries a lower risk of oral cancer than does continued smoking and has virtually no other consequential adverse effects. In fact, the annual incidence rate of oral cancer among American ST users has been estimated at 26 cases per 100,000 person-years. This is a relative risk of 4.2 compared with nonusers of tobacco. 18 If the nation's current 46 million smokers instead used ST, then 12,000 new cases of oral cancer would occur annually, 19 based on an incidence rate of STinduced oral cancer of 26 cases per 100,000 long-term users. 18 These 12,000 cases represent less than 5% of all smoking-related cancers, less than 10% of smoking-related lung cancers, and less than 50% of the 27,000 cases of oral cancers now attributed to smoking each year. Thus the substitution of ST for cigarettes would result in a substantial reduction in all tobacco-related health effects, including oral cancer. Although oral cancer has about a 50% mortality rate, the 6,000 deaths that would result pales in comparison with the number of people who die each year from the health consequences of smoking. Currently, 419,000 Americans die yearly from smoking-related illnesses including cardiovascular disease (180,000), cancer (148,000), and respiratory disease (85,000). 54 A recent analysis of American data confirms that the impact of ST use on life expectancy is minimal. 55 The study revealed that both ST users and nontobacco users have an average life expectancy that is 8 years longer than cigarette smokers. In one of the largest series of oral cancer cases related to ST use, the average age at diagnosis was 78 years (as opposed to an average age of 60 years for smoking-related head and neck cancer) 3, 29 and followed an average of 55 years of ST use. 56
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY August 1995 Some critics charge that a switch from smoking to ST use is a trade of body parts, lung cancer for oral cancer. There is no trade; about 90% of the oral cancer cases seen in the United States are attributable to smoking 57 and only about 5% are related to ST use. By direct comparison, the relative risk (RR) of oral cancer from ST use (RR = 4.2) 18 is about half that of the risk from smoking (RR = 10 to 15). 58 The RR of oral cancer with ST use is often misrepresented. For example, a frequent comment is " S T users are 50 times more likely to develop oral cancer than abstainers."59 This high RR estimate pertains only to gingival cancer, a rare form of oral cancer, and only after more than 50 years of use. 18 When examining a rare phenomenon, such as gingival cancer, small changes in the number of cases, or even chance, will produce highly variable risk estimates. This is exemplified by the fact that the 95% confidence interval for the 50-fold increased risk extends from 9 to 250.18 Recommending a switch from cigarette smoking to ST has also elicited ethical concerns. 6~ 61 In considering these concerns it is important to remember that recommendations from health professionals almost always involve a tradeoff of risks and benefits. For example, radiation and chemotherapy are standard cancer treatment options even though they cause disease, some as severe as a second malignancy. The same principle applies to strategies in preventive medicine. Tamoxifen, an estrogen antagonist, is under study by the National Cancer Institute as a prophylactic measure for primary breast cancer in highrisk women. 62 Although tamoxifen may reduce the risk of breast cancer, it increases the risk of uterine cancer 7.5-fold. 62 However, the National Cancer Institute considers the risk/benefit balance favorable enough to justify the study. 62 A switch to ST use for inveterate smokers can be similarly justified--if not ethically mandated. Full adoption of this strategy would eventually save over 400,000 lives each year, a 98% reduction in deaths from all tobacco-related illnesses. This proposal is not an invitation to nonusers of tobacco to start; it is intended solely as a risk reduction strategy for the current smoker. The message is directed at adult smokers as an alternative to conventional cessation programs and nicotine substitution. Sadly, current smoking cessation programs end in failure for over 75% of smokers who try them. Although all tobacco use carries some risk, a reduction in risks for these inveterate smokers by a switch to ST will save lives. With one in five Americans dying from smoking-related illnesses, it is imperative to implement any strategy that can significantly reduce mortality.
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Volume 80, Number 2 REFERENCES 1, Parkin DM, Laara E, Muir CS. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 1988; 41:184-97. 2, Boring CC, Squires TS, Tong T. Cancer statistics, 1994. CA Cancer J Clin 1994;44:7-26. 3. Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988;48:3282-7. 4. Hill C, Benhamou E, Doyan F. Trends in cancer mortality, France 1951-1985. Br J Cancer 1991;63:587-90. 5. Centers for Disease Control and Prevention. Use of smokeless tobacco among adults, United States 1991. MMWR Morb Mortal Wldy Rep 1993;42:263-6. 6. Connolly GN, Orleans CT, Kogan M. Use of smokeless tobacco in major league baseball. N Engl J Med 1988;318:1281-5. 7. Connolly GN, Orleans CT. Snuffing tobacco out of sport. Am J Public Health 1992;82:351'3. 8. Pro sports and smokeless tobacco. Am Fam Physician 1987; 35:97. 9. Poulson TC, Lindenmuth JE, Greer RO Jr. A comparison of the use of smokeless tobacco in rural and urban teenagers: CA Cancer J Clin 1984;34:248-61. 10. Grady D, Greene J, Daniels TE, et al. Oral mucosal lesions found in smokeless tobacco users. J Am Dent Assoc 1990; 121:117-23. 11. Sinusas K, Coroso JG, Sopher MD, Carbtree BF. Smokeless tobacco use and oral pathology in a professional baseball organization. J Fam Pract 1992;34:713-8. 12. Greene JC, Ernster VL, Grady DG, Robertson PB, Walsh MM, Stillman LA. Oral mucosal lesions: clinical findings in relation to smokeless tobacco use among U.S. baseball players. monograph 2. Smokeless tobacco or health: an intemational perspective. NIH publication No. 93-3461:41-50, 1993. 13. Hirayama T. An epidemiological study of oral and pharyngeal cancer in Central and South-East Asia. Bull World Health Organ 1966;34:41-69. 14. Muir CS, Zaridze DG. Smokeless tobacco and cancer: an overview. Lyon, France: International Agency for Research on Cancer Scientific Publications, 1986;74:35-44. 15. AMA Council on Scientific Affairs. Health effects of smokeless tobacco. JAMA 1986;255:1038-44. 16. Squier CA. Smokeless tobacco and oral cancer: A cause for concern? CA Cancer J Clin 1984;34:242-7. 17. Peacock EE Jr, Greenberg BG, Brawley BW. The effect of snuff and tobacco on the production of oral carcinoma: an experimental and epidemiological study. Ann Surg 1960; 151: 542-50. 18. Winn DM, Blot WJ, Shy CM, Pickle LW, Toledo A, Fraumeni JF. Snuff dipping and oral cancer among women in the southern United States. N Engl J Med 1981;304:745-9. 19. Rodu B. An alternative approach to smoking control. Am J Med Sci 1994;308:32-4. 20. Palmer C. Dr. Novello targets smokeless. ADA News. January 4, 1993:16. 21. World Health Organization. Definition ofleukoplakiaandrelated lesions: an aid to studies on oral precancer. ORAL SURG ORAL MED ORAL PATHOL 1978;46:518-39. 22. Axell T, Holmstrup P, Kramer IRH, Pindborg JJ, Shear M. International seminar on oral leukoplakias and associated lesions related to tobacco habits. Community Dent Oral Epidemiol 1984;12:145-54. 23. Bouquot JE. Reviewing oral leukoplakia: clinical concepts for the 1990s. J Am Dent Assoc 1991;122:80-2. 24. Anderson G, Axell T. Clinical appearance of lesions associated with the use of loose and portion-bag packed Swedish moist snuff: a comparative study. J Oral Pathol Med 1989; 18:2-7. 25. Greer RO, Poulson TC. Oral tissue alteration associated with the use of smokeless tobacco by teen agers: Part 1. clinical findings. OVALSta~GORALMED ORALPATHOL1983;56:275-84. 26. Greer RO, Poulson TC, Boone ME, Lindenmuth JE, Crosby
27.
28.
29. 30. 31.
32. 33. 34. 35.
36. 37. 38.
39. 40. 41.
42. 43. 44.
45.
46. 47.
48.
L. Smokeless tobacco associated oral changes in juvenile, adult, and geriatic patients: clinical and histomorphologic features. Gerodontics 1986;2:87-98. Bouquot JE, Weiland L, Ballard D, Kurland L. Leukoplakia of the mouth and pharynx in Rochester, Minnesota, 19351984: incidence, clinical features, and follow-up of 463 patients from a relatively unbiased patient pool. J Oral Pathol 1988; 17:436. Bouquot JE, Gorlin RJ. Leukoplalda, lichen planus, and other oral keratoses in 23,616 white Americans over the age of 35 years. ORALSURGORALMEt) ORALPATHOL 1986;61:37381. Silverman S, Gorsky M. Epidemiologic and demographic update in oral cancer: California and national data 1973 to 1985. J Am Dent Assoc 1990;120:495-9. Waldron CA, Shaffer G. Leukoplakia revisited: a clinicopathologic study 3256 of oral leukoplakias. Cancer 1975;36: 1386-92. Bouquot J, Schhhroeder K. Oral leukoplakia and smokeless tobacco keratoses are two separate and distinctive precancers. ORAL SURG ORAL MED ORAL PATHOL 1993;76:588-9. Smith JF, Mincer HA, Hopkins KP, Bell J. Snuff-dipper's lesion: a cytological and pathological study in a large population. Arch Otolaryngol 1970;92:450-6. Roed-Petersen B, Pindborg JJ. A study of snuff-induced oral leukoplakias. J Oral Pathol 1973;2:301-13. Axell T, Momstad H, Sundstrom B. The relation of the clinical picture to the histopathology of snuff dipper's lesions in a Swedish population. J Oral Pathol 1976;5:229-36. Mincer HH, Coleman SA, Hopkins KP. Observations on the clinical characteristics of oral lesions showing histologic epithelial dysplasia. ORALSUR6 ORALMED ORALPATHOL 1972; 33:389-99. Kaugars GE, MehailescU WL, Gunsolley JC. Smokeless tobacco use and oral epithelial dysplasia. Cancer 1989;64:152730. Smith JF. Snuff-dippers' lesions: a ten-year follow-up. Arch Otolaryngol 1975;101:276-7. Christen AG, McDonald JL, Christen JA. The impact of tobacco use and cessation on nonmaligant and precancerous oral and dental diseases and condition. Indianapolis: Indiana University School of Dentistry teaching monograph. Precancerous condition. June 1991:7-13. Chen SY. Effects of smokeless tobacco on the buccal mucosa of HMT rats. J Oral Pathol Med 1989;18:108-12. Park NH, Sapp JP, Herbosa EG. Oral cancer induced in hamsters with herpes simplex infection and stimulated snuff dipping. ORAL SURG ORAL MED ORAL PATHOL 1986;62:164-8. Silverman S, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation: a follow-up study of 257 patients. Cancer 1984;36:563-8. Sankaranarayanan R, Nair MK, Mathew B, Balaram P, Sebastian P, Chandra Dutt S. Recent results of oral cancer research in Kerala, India. Head Neck 1992;14:107-12. Brunnemann KD, Genoble L, Hoffmann D. N-Nitrosamines in chewing tobacco: an international comparison. J Agric Food Chem 1985;33:1178-81. Brnnnemann KD, Hoffmann D. Chemical composition of smokeless tobacco products. Monograph 2. Smokeless tobacco or health: an international perspective. NIH publication No: 93-3461:96-105, 1993. Wary KK, Sharan RW. Aqueous extract of betel nut of northeast India induces DNA-strand breaks and enhances rate of cell proliferation in vitro: effects of betel-nut extract in vitro. J Cancer Res Clin Oncol 1988;114:579-82. Thomas SJ, MacLennan R. Slaked lime and betal nut cancer in Papua, New Guinea. Lancet 1992;340:577-8. Jayant K, Balakrishhhnan V, Sanghvi LD, Jussawalla DJ. Quantification of the role of smoking and chewing tobacco in oral, pharyngeal, and oesophageal cancers. Br J Cancer 1977; 35:232-4. Marcus AC, Crane LA, Shopland DR, Lynn WR. Use of
182
Vigneswaran et al.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
August 1995
49.
50. 51. 52. 53.
54. 55. 56.
57.
58.
smokeless tobacco in the United States: recent estimates from the current population survey. NCI monograph 1989;8: 17-23. Mason TJ, McKay FW. US Cancer mortality by county: 1950-1969. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, DHEW Publication No. (NIH) 74-615, 1974. Nordgren P, Ramstrom L. Moist snuff in Sweden: tradition and evolution. Br J Addict 1990;85:1107-12. La Vecchia C, Lucchini F, Negri E, Boyle P, Malsonneuve P, Levi F. Trends of cancer mortality in Europe, 1955-1989: I. digestive sites. Eur J Cancer 1992;28:132-235. Axell T, Mornstad H, Sundstrom B. Snuff and cancer of the oral cavity: a retrospective study. Lakartidningen 1978;75: 1224-6. La Vecchia C, Lucchini F, Negri E, Boyle P, Maisonneuve P, Levi F. Trends of cancer mortality in Europe, 1955-1989: II. respiratory tract, bone, connective and soft tissue sarcomas, and skin. Eur J Cancer 1992;28:514-99. Centers for Disease Control. Cigarette smoking-attributable mortality and years of potential life lost: United States, 1990. MMWR Morb Mortal Wkiy Rep 1993;42:645-9. Rodu B, Cole P, Tobacco-related mortality. Nature 1994; 370:184. McGuitt WF, Wray A. Oral carcinoma and smokeless tobacco use: a clinical profile. Monograph 2. Smokeless tobacco or health: an international perspective. NIH publication No. 933461:91-5, 1993. US Department Of Health and Human Services. The health consequences of smoking: 25 years of progress. A report of the Surgeon General, U.S. Department of Health and Human Services. Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. DHHS Publication No. (CDC) 89-8416:1990. Stockwell HG, Lyman GH. Impact of smoking and smokeless
59. 60. 61. 62.
tobacco on the risk of cancer of the head and neck. Head Neck Surg 1986;9:104-10. Blowing smoke at Congress. New York Times. April 17, 1994. Nelson C. University of Alabama smokeless tobacco study under fire. JNCI 1994;86:1193, Jacob JA. Smokeless advice 'irresponsible'. ADA News, October 3, 1994. Taylor R. Trials and errors in breast-cancer research. J NIH Res 1994;6:27-30.
Reprint requests: Brad Rodu, DDS SDB 81 UAB Birmingham, AL 35294-0007
Editor's Note: We realize that the material presented by Dr. Vigneswaran and colleagues represents an area of biomedical science that has the potential to elicit strong emotions. Science should not be based solely on emotion, however, and these investigators have examined the problem of tobacco use and carcinogenesis from a perspective that may seem foreign to many of our readers. Nevertheless, in the spirit of scientific inquiry', we invite the readership to comment on the concepts proposed in this article. Selected letters will be published together with the authors' responses in a future issue.
Carl M. Allen, DDS, MSD Oral and Maxillofacial Pathology Section