AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

The use of smokeless tobacco is associated with a spectrum of oral cavity lesions, including leukoplakia, speckled leukoplakia, erythroplasia, tobacco-associated keratosis, carcinoma in situ (CIS), verrucous carcinoma, and invasive squamous cell carcinoma (SCC). In addition to oral lesions, smokeless tobacco users are at increased risk for stomach and pancreatic cancers, although the data regarding the risks for pancreatic cancer are mixed, with some studies showing a statistical association.^{1, 2, 3, 4}

The term smokeless tobacco, also known as dip, plug, chew, or spit tobacco, refers to both chewing tobacco (coarse cut) and snuff (fine cut). Snuff may be used in a dry form, which is inhaled nasally, or in the more commonly used moist form, which is placed in the oral cavity. Recently, "pouch" tobacco products have been marketed to the public. This type of tobacco is positioned along the gum line, and the user may swallow the juices, making chewing and spitting unnecessary. In the United States, clean indoor air acts and cigarette excise tax increases have resulted in a coincidental increase in smokeless tobacco use.⁵

Tobacco-related lesions (smokeless tobacco–related and nicotinic stomatitis) recently comprised 4.7% of all lesions found in 17,235 people examined as part of the Third National Health and Nutrition Examination Survey. Smokeless tobacco users had one of the highest odds of having a lesion present (odds ratio, 3.9).⁶

Oral leukoplakia (white plaques) is a common physical finding in 40-50% of people who use smokeless tobacco. It is a premalignant lesion, with the risk of malignant transformation to oral cancer varying in relation to the product used. In relation to snuff products, differences in the tobacco species, fermentation process, nicotine content, tobacco-specific N-nitrosamines content, and pH may account for the differences in the reported risk. With most products, the risk appears quite low, whereas Toombak dipping has been associated with a high incidence of oral cancer in the Sudan.^{7, 8} Oral leukoplakia has been shown to regress in as few as 6 weeks with smokeless tobacco cessation.⁹ See Leukoplakia, Oral for more information.

Erythroplasia (ie, erythroplakia, red plaques) is associated with severe dysplasia or malignancy in 80-90% of cases. Because of the high malignancy rate, the threshold for histologic evaluation of erythroplasia should be low.

Speckled leukoplakia is much less common than either leukoplakia or erythroplasia and is distinguished, as the name suggests, by a speckled appearance.

Tobacco-associated keratosis is a predictable lesion that manifests as an area of thickening at the site of habitual placement of snuff or chewing tobacco. Two distinct grading systems are used to classify lesion stage by degree of clinical thickening. The development of a lesion is dependent on the amount, frequency, type, and brand of smokeless tobacco used.

CIS may manifest clinically as leukoplakia, erythroplasia, speckled leukoplakia, or tobacco-associated keratosis.

SCC may arise in areas of oral or speckled leukoplakia, erythroplasia, or verrucous carcinoma. More than 80% of patients with oral SCC smoke, although those who smoke pipes or cigars are at the greatest risk. Overall, SCC accounts for more than 90% of all oral cancers. See Squamous Cell Carcinoma for more information.

Verrucous carcinoma (also known as snuff dipper's cancer) is a type of low-grade, slow-growing, exophytic SCC that arises from regions in the mouth where smokeless tobacco is consistently placed. Lesions rarely metastasize but may recur, and, rarely, they transform into invasive SCCs. Although verrucous carcinoma is not the most common oral lesion found in users of smokeless tobacco, most cases of verrucous carcinoma are diagnosed in habitual users of smokeless tobacco. See Verrucous Carcinoma for more information.

Pathophysiology

Oral smokeless tobacco contains numerous carcinogens, including polonium 210, tobacco-specific N-nitrosamines, volatile aldehydes, and polycyclic aromatic hydrocarbons.

An analysis of the nicotine content of 11 brands of popular smokeless tobacco products found that moist snuff has the highest nicotine content, whereas loose-leaf chewing tobacco has the lowest nicotine content.¹⁰

Pure nicotine and smokeless tobacco extract have been compared for their oxidative stress actions by measuring the generation of reactive oxygen species. Pure nicotine has been found to be less toxic than smokeless tobacco extract with equivalent amounts of nicotine.¹¹

Approximately twice as much nicotine is absorbed per dose from smokeless tobacco than cigarettes (4 mg vs 2 mg); orally absorbed nicotine also stays longer in the bloodstream. The average can of smokeless tobacco has an estimated nicotine content of 144 mg, equal to 80 cigarettes. Smokeless tobacco that is placed in the mucobuccal folds causes direct damage to the periodontium (eg, gingivitis, periodontal recession) and oral soft tissue.

Frequency

United States

Smokeless tobacco and its associated lesions affect a large number of persons in the United States, with an estimated 7-13 million people who use smokeless tobacco annually. The popularity of oral forms of snuff and chewing tobacco has rapidly increased in North America, especially among white adolescent males, with an increasing national prevalence in this group from 0.7% in 1970 to 7.5% in 1991.

The percentage of male high school students who used smokeless tobacco on at least 1 of the 30 days preceding a Youth Risk Behavior Survey published in 2003 by the US Centers for Disease Control and Prevention (CDC) varied by state. State prevalence rates in order of descending frequency were 21-30% for Alabama, Kentucky, Tennessee, West Virginia, Arkansas, Montana, Wyoming, and Oklahoma; 11-20% for South Dakota, North Dakota, South Carolina, Kansas, Idaho, Mississippi, Alaska, Colorado, Iowa, Indiana, Nebraska, New Mexico, Wisconsin, Ohio, Texas, Missouri, New Hampshire, Michigan and Maine; and less than 10% for Florida, Arizona, Massachusetts, Delaware, Nevada, New York, Rhode Island, and Maryland.

In 1999, the Journal of the American Medical Association published state-specific prevalences of cigarette and smokeless tobacco use among adults compiled by the CDC from the 1997 Behavioral Risk Factor Surveillance System.⁵ Health behaviors were assessed through a random-digit dialing telephone survey, and responders were asked if they have ever used or are currently using chewing tobacco or snuff. Results of 17 states were published, revealing more than a 6-fold difference in prevalence rates between Arizona and West Virginia (1.4% vs 8.8%, respectively). The states with the highest prevalence rates were West Virginia and Wyoming (the prevalence rates in males were 18.4% and 14.7%, respectively). In males, prevalence rates of 9-12% were reported in Alabama, Alaska, Kansas, Kentucky, and Montana. Smokeless tobacco use among women was less than or equal to 1.7% in all 17 states.

According to the American Cancer Society, approximately 34,360 new cases (24,180 in men and 10,180 in women) of oral cavity and oropharyngeal cancer will be diagnosed in the United States in 2007, and approximately 7,550 people (5,180 men and 2,370 women) will die in 2007 as a result of these cancers. The death rate for oral cancer is higher than that for malignant melanoma, Hodgkin disease, brain cancer, testicular cancer, or cervical cancer, but it has been decreasing over the past 30 years. Oral cancer is 4 times more likely to occur in users of smokeless tobacco than in those who do not use tobacco products. The annual incidence of oral cancer is estimated at 26 cases per 100,000 users of smokeless tobacco.

International

Worldwide, more than 350,000 new cases of oral and laryngeal cancers are diagnosed each year. Rates of oral cancer vary among countries, with Hungary and France having higher incidences than the United States, and Japan and Mexico having much lower rates.

Mortality/Morbidity

• The survival rates associated with oral SCCs vary from 30-100%, depending on the size, the time of diagnosis, and the location of the lesion. Invasive SCC metastasizes via lymphatic spread, usually to the cervical lymph nodes.
• In 1993, Wray and McGuirt¹² described a 5-year survival rate of 37% in patients who used smokeless tobacco for 40 years or more.
• Decreased survival rates from smokeless tobacco use are not likely due to oral cancer alone but include other causes of morbidity and/or mortality. Small studies in specific ethnic populations have shown an increased risk of cardiovascular disease.¹³

Race

Currently, the incidence of oral cancer is slightly more common in blacks than in whites. From 1987-1992, the incidence of oral cancer was 10.4 cases per 100,000 whites and 13.9 cases per 100,000 African Americans. 

Sex

Oral cancer is more commonly diagnosed in men than in women. In 2004, 10,270 new male cases of oral and tongue cancer were reported in the United States, compared with 7,130 new female cases.

Age

Smokeless tobacco use usually begins between ages 9 and 16 years. Although the use of smokeless tobacco frequently starts at school age and may continue in middle age, oral cancer is most commonly diagnosed in patients aged 65 years or older. Verrucous carcinoma, specifically, is most commonly diagnosed in men older than 50 years.

The average age of most people diagnosed with cancer of the oral cavity is 62 years, but approximately 30% of these cancers occur in patients younger than 55 years.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Patients may present asymptomatically, admitting only to the use of smokeless tobacco or to the presence of other predisposing risk factors (eg, use of alcohol, exposure to chronic irritants) for premalignant and cancerous lesions. In more advanced disease, patients may report pain, swelling, or dysphagia.

Physical

Leukoplakia

Leukoplakia refers to a filmy white or yellow patch involving the oral mucosa. The patch may appear translucent or opaque and raised or ulcerated. It may be pumicelike. Leukoplakia is a clinically descriptive term, and other diseases must be ruled out.

Erythroplasia 

Erythroplasia appears as a patch with varying degrees of erythema. It most commonly occurs on the floor of the mouth.

Speckled leukoplakia 

The lesions are white patches with interspersed areas of erythema. Two thirds of the lesions are located on the buccal mucosa; the tumors are commonly nodular.

Tobacco-associated keratosis 

Tobacco-associated keratosis is an ill-defined area of white thickening at the sites at which oral smokeless tobacco is habitually placed; most commonly, these areas involve the mandibular labial and buccal mucosal folds. The continued use of smokeless tobacco causes the affected areas to become corrugated and grayer.

Verrucous carcinoma 

The lesions appear as exophytic growths with papillary projections, they may be large at the time of diagnosis, and they can cause local tissue destruction. They appear rough surfaced with a broad-base attachment.

Squamous cell carcinoma 

The lesions usually have a mixed red and white appearance, with ulceration or inflammation in some cases. The lesions are most commonly found on the floor of the mouth and on the ventral and lateral surfaces of the tongue. Those cancers associated with smokeless tobacco may arise in differing locations associated with quid placement and/or the buccal folds. Swelling or induration is characteristic of invasive growth.

Causes

Alcohol consumption, cigarette smoking, candidal infection, and poor dentition are causes. Additionally, human papillomavirus (HPV), especially HPV 16, has been implicated in the pathogenesis of 20-30% of oropharyngeal cancers. People with HPV-related oral cancers seem to have a better prognosis than those without HPV infection, and they are less likely to have a history of tobacco and alcohol use. Finally, exposure to chronic irritants (eg, mouthwash, poorly fitting dentures) may be associated with oral mucosal cancer.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Chronic hyperplastic candidiasis
Focal frictional hyperkeratosis
Idiopathic leukoplakia
Leukoedema
Traumatic ulceration
White hairy tongue
White sponge nevus

Keratoacanthoma is a benign epithelial proliferation from unknown causes. It is usually found on the vermilion border, but it may also occur on the oral mucosa. It appears as a firm, white nodule with a roughened, central region. It grows rapidly and then stabilizes or regresses in size. Histologically, it appears as epithelial thickening with a central plug, without evidence of atypia.

Nicotinic stomatitis is a diffuse, rough, white thickening with erythematous papules on the hard palate caused by exposure to heat from smoke or burning tobacco. The lesions may also present as umbilicated nodules with central red spots. The erythematous papules or red spots are caused by irritation to the openings of the minor salivary glands. Stomatitis is asymptomatic, benign, and typically found in middle-aged and elderly men. When biopsy samples are obtained, the epithelium shows reactive hyperplasia with ductal squamous metaplasia and chronic inflammation. See Nicotine Stomatitis for more information.

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

No blood tests are available to help diagnose cancers of the oral cavity.

Imaging Studies

Typically, imaging studies are reserved for staging purposes once oral cancer has been diagnosed. Chest radiography, barium swallow, MRI, and positron emission tomography scanning may be used to rule out the involvement of other organ systems.

Other Tests

A thorough history, including an assessment of the risk factors, and a careful examination of the oral cavity are the most important clinical tools in diagnosing oral lesions. The physical examination must include an assessment of the cervical lymph nodes.

Procedures

In order to better visualize lesions of the throat, base of the tongue, and larynx, indirect pharyngoscopy and laryngoscopy may be performed. In addition, if suspicion for a head or neck cancer is strong, endoscopy may be performed to more thoroughly examine the oral cavity, oropharynx, larynx, esophagus, trachea, and bronchi.

Exfoliative cytology of a suggestive lesion may be performed, but oral cancer can only be definitively diagnosed based on findings from an incisional biopsy.

Histologic Findings

Tobacco-associated keratosis appears as epidermal thickening or hyperkeratosis and acanthosis. Dysplasia is uncommon in this lesion.

Leukoplakia appears as hyperkeratosis due to chronic irritation in approximately 80% of cases. A minority of lesions shows precancerous changes with varying degrees of dysplasia.

Speckled leukoplakia exhibits both epithelial hyperplasia and epithelial atrophy. Dysplasia occurs in 50-70% of all lesions, but carcinoma is rarely diagnosed. Candidal infection may be a common finding, with an inflammatory infiltrate of lymphocytes and plasma cells in the underlying connective tissue. The role of candidal species in causation of the lesion is unclear.

Erythroplasia shows mild-to-moderate epithelial dysplasia in only 9% of lesions obtained from biopsy samples. Severe dysplasia, CIS, or SCC is often apparent. The clinical size of the lesion is not correlated with microscopic severity.

CIS refers to severe dysplasia extending the full thickness of the epithelium. Grossly, CIS may appear as leukoplakia, speckled leukoplakia, erythroplasia, or keratosis.

At histologic examination, SCC shows increased cellular proliferation, atypical mitotic figures, loss of cell cohesion, and/or atypical keratinization. Invasive growth is indicated by the invasion of tumor cells into the epithelial basement membrane. Verrucous carcinoma is a specific form of SCC that exhibits a high level of differentiation.

Staging

See the American Cancer Society detailed guide on oral cavity and oropharyngeal cancer: "How Are Oral Cavity and Oropharyngeal Cancers Staged." 

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

To reduce the risk of progression to oral cancer, smokeless tobacco use should be minimized, with cessation encouraged. The National Cancer Institute recommends that clinicians use the "4 A's," as follows:

• Ask about tobacco use
• Advise patients to quit smoking
• Assist patients in quitting
• Arrange follow-up

Both the nicotine patch (in variable doses) and bupropion are helpful in treating nicotine dependence, with an additive effect when used in combination. Other medications useful in treating nicotine dependence include nicotine nasal spray inhalers; nicotine gum; and nontobacco snuff products containing mint, clover, alfalfa, and flavorings.

In 2000, Horn and colleagues¹⁴ reported that West Virginian athletes were particularly vulnerable to smokeless tobacco use. The study concluded that both middle and high school coaches were willing to help athletes quit and should act as smokeless tobacco intervention agents.

The National Spit Tobacco Education Program (NSTEP)¹⁵ is a national organization committed to minimizing the risk of oral cancers associated with smokeless tobacco through education. This organization does not advocate smokeless tobacco use as a healthier alternative to cigarette smoking. NSTEP targets education to the general public and specifically to baseball players and their families, in whom the use of smokeless tobacco is extremely high. In fact, NSTEP is supported and endorsed by both Major League Baseball and Little League Baseball.

Surgical Care

Biopsy should be performed on lesions of erythroplasia that are suggestive of cancer based on their appearance or location in the oral cavity or those that have failed to resolve within 2-3 weeks. Premalignant lesions and CIS may be permanently cured after excision or biopsy. Primary and invasive SCCs are treated with varying combinations of surgery and/or radiation.

Once a diagnosis of oral cancer is established, the therapeutic approach is multidisciplinary.

Consultations

Treatment for oral cancer may involve consultation with the following:

• Maxillofacial surgeon
• Speech therapist
• Dentist
• Radiation oncologist

Diet

A poor diet has been related to the development of oral cancer, but the substances in healthy foods responsible for this difference remain unclear.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Both the nicotine patch (in variable doses) and bupropion are helpful in treating nicotine dependence, with an additive effect when used in combination. Other medications useful in treating nicotine dependence include nicotine nasal spray inhalers; nicotine gum; nicotine lozenges; and nontobacco snuff products containing mint, clover, alfalfa, and flavorings. In addition, varenicline was approved by the US Food and Drug Administration in 2006 to help cigarette smokers quit. It also may help users of smokeless tobacco quit by decreasing their withdrawal symptoms.

A case published in the Journal of the American Medical Association was the first to document the efficacy of bupropion for the treatment of smokeless tobacco addiction.¹⁶ A 31-year-old man, with a history of a 1 can/d use of smokeless tobacco for 11 years, had previously attempted to quit using nicotine patches and abrupt cessation. He underwent a 4-week course in behavior modification including coping strategies and maintenance skills and set a quit date. Bupropion (150 mg bid) was started 1 week prior to group therapy and was continued for 10 weeks total. After 1 week, his cravings were reduced, and at 5 weeks, he was tobacco free. The patient remained tobacco free at 8 months.

The following Medscape CME courses may be of interest:

• Varenicline May Be Better Than Transdermal Nicotine Replacement to Quit Smoking
• "Cut Down to Quit" -- New Designation for Nicotine Replacement Therapy: A Best Evidence Review

Drug Category: Smoking deterrents

These agents are used to aid in smoking cessation, while the patient participates in a behavioral modification program under medical supervision.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Outpatient Care

Persons who use smokeless tobacco should have regular follow-up visits to their physician and dentist for oral examinations.

In/Out Patient Meds

See Medication.

Deterrence/Prevention

NSTEP, with funding from the Robert Wood Johnson Foundation and other national organizations, advocates the prevention of smokeless tobacco use through education. Additionally, Clinicians should use the "4 A's" proposed by the National Cancer Institute as outlined in Medical Care.

Prognosis

The prognosis for oral cancer varies greatly with the location and the size of the tumor at the time of diagnosis. The survival rates are 90-100% for small carcinomas in the hard palate, on the upper part of the gingiva, on the floor of the mouth, and on the buccal mucosa. Moderately advanced lesions without spread to the lymph nodes are associated with a local control rate of as much as 80%, whereas posterior cancers that appear late are associated with a survival rate as low as 30%.

Patient Education

Patient handouts regarding smoking cessation techniques and resources (eg, setting a quitting date, group therapy) are available from the National Cancer Institute. Additionally, the National Spit Tobacco Education Program provides patient resources and a list of activities by region.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Cancer of the Mouth and Throat.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

Failure to diagnose a malignant lesion could be a medicolegal issue.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Editor-in-Chief, William James, MD, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Verrucous carcinoma.
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Media file 2:  Oral leukoplakia.
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REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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Article Last Updated: Nov 12, 2008