This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Note: Separate PDQ summaries on Oral Cancer Screening; Lip and Oral Cavity Cancer Treatment; and Cigarette Smoking: Health Risks and How to Quit are also available.
Who is at Risk?
People who use tobacco in any of the commonly available forms (cigarettes, cigars, pipes, and smokeless tobacco) or have high alcohol intake are at elevated risk of oral cancer; and they are at particularly high risk if they use both tobacco and alcohol. People who chew betel quid (whether mixed with tobacco or not)—a common practice in south central Asia and Melanesia—are also at high risk. Individuals with persistent oral infection by carcinogenic strains of human papillomavirus (HPV) are also at increased risk. People with chronic sun exposure are at elevated risk of lip cancer, particularly on the lower lip.
Factors associated with increased risk of oral cancer
Based on solid evidence from numerous observational studies, tobacco use causes cancers of the lip, oral cavity, and oropharynx.[1,2,3] Smoking avoidance and smoking cessation result in decreased incidence and mortality from oral cancer.
Magnitude of Effect: Large (most cancers of the oral cavity are attributable to the use of tobacco products).
Based on solid evidence, alcohol use is an independent risk factor for the development of oral cancer.[4,5,6,7]
Magnitude of Effect: Lower than the risk associated with tobacco use, but the risk is approximately doubled for people who drink three to four alcoholic beverages per day compared to nondrinkers, and is dose related.
Oral cancer risk is highest in persons using both alcohol and tobacco compared with those using one or the other.
Based on solid evidence, there is a strong association between oral HPV infection and oral cancer, particularly HPV type 16.[8,9,10,11] Given the known causal association between HPV infections and cancer of the cervix, the established strong association between infection by carcinogenic strains of HPV and oral cancer may also be causal.
Magnitude of Effect: Not well quantified. It accounts for a small but increasing proportion of oral cancers.
Based on fair evidence, carcinoma of the lip, predominantly the lower lip, is associated with sun exposure.[12,13,14]
Magnitude of Effect: Not well quantified due to wide confidence intervals.
Interventions Associated With a Decreased Risk of Oral Cancer
Avoidance of tobacco
Based on solid evidence, avoidance or cessation of exposure to tobacco (e.g., cigarettes, pipes, cigars, and smokeless tobacco) would lead to a decrease in oral cancer.
Magnitude of Effect: Decreased risk, moderate to large magnitude.
Interventions With Inadequate Evidence as to Whether They Reduce the Risk of Oral Cancer
Avoidance of alcohol
Although alcohol use is a risk factor for oral cancer and, by inference, its avoidance would lead to fewer cases, there is inadequate empiric evidence that cessation of alcohol use decreases the risk of oral cancer.
Magnitude of Effect: Decreased risk, moderate magnitude.
Avoidance of HPV infection
Although infection with specific carcinogenic strains of HPV is a risk factor for (and likely causes) a subset of oral cancers and, by inference, its avoidance would lead to fewer cases, there is inadequate empiric evidence that strategies to avoid infection decrease the risk of oral cancer.
Magnitude of Effect: Not defined.
There is inadequate evidence to determine whether a change in diet would decrease the risk of oral cancer.
Magnitude of Effect: Not applicable (N/A).
Sun avoidance and sunscreen use
There is inadequate evidence to determine whether reducing sun exposure or use of sunscreens would prevent lip cancer. (Refer to the PDQ summary on Skin Cancer Prevention for more information about sun avoidance and sunscreen use for prevention of skin cancer.)
Magnitude of Effect: N/A.
Incidence and mortality
Over the period from 2004 to 2008, the estimated incidence of oral cancer in the United States was 10.6 cases per 100,000 persons per year. The most recent estimated mortality rate (from 2003–2007) was 2.5 per 100,000 persons per year. U.S. incidence and mortality rates are about 2.5 and 2.8 times higher, respectively, in men than women. It is estimated that there will be 40,250 new cases of oral cancer diagnosed in the United States in 2012 and 7,850 deaths due to this disease. The estimated age-standardized (World Standard Population) worldwide incidence and mortality rates of oropharyngeal cancer in 2008 were 5.9 and 3.3 per 100,000 persons per year, respectively. Primarily due to differences in tobacco and alcohol use, there is wide variation in rates across the world. South central Asia and Melanesia have particularly high rates of oral cancer attributable to betel quid chewing, and Australia has a high rate of lip cancer attributed to solar irradiation.
Oral cancer can be divided into three clinicopathological categories: carcinoma of the lip vermillion, carcinoma of the oral cavity proper, and carcinoma of the oropharynx.
Squamous cell carcinoma, which arises from the oral mucosal lining, accounts for more than 90% of the tumors in the oral cavity and oropharynx. Other types of primary tumors arising in this area include lymphoma, sarcoma, melanoma, and minor salivary gland tumors. In the Western world the most common locations of tumor development are the tongue and floor of the mouth; however, in parts of the world where tobacco or betel quid chewing is prominent, cancers of the retromolar trigone and buccal mucosa are common. Oral squamous cell carcinomas are sometimes preceded by oral preneoplastic lesions, which are often present as visible alterations of the mucosal surface and include leukoplakia and erythroplakia.
The most important factor affecting long-term outcome after treatment is the stage of disease at diagnosis; however, overall outcome is stage and site dependent. Although early-stage tumors (without lymph node involvement) have an excellent anticipated 5-year survival rate (about 82%), the 5-year survival rates for patients with regional lymph node spread or metastases are only about 56% and 34%, respectively. Some or all of the differences in prognosis among disease stages may be due to lead-time bias rather than a benefit of early detection and treatment. (Refer to the PDQ summary on Cancer Screening Overview for more information.)
Tobacco use is responsible for more than 90% of tumors of the oral cavity among men and 60% among women, and is responsible for 90% of oral cancer deaths in males. All forms of tobacco—cigarettes, pipes, cigars, and smokeless tobacco—have been implicated in the development of oral cancers. While tobacco confers the highest risk for cancer of the floor of the mouth, it is associated with an increased risk for all sites of oral cancer.
Tobacco use is known to cause "field cancerization" resulting in a propensity for development of second primary tumors in patients with oral cancer. Case reports have also implicated marijuana smoking as a cause of oral cancer, particularly in younger patients.
Alcohol use is a second independent major risk factor for the development of oral cancer.[11,12,13,14] There is a suggestion that beer and hard liquor confer a greater risk than wine. The risk of oral cancer increases with the number of cigarettes smoked per day and the number of alcoholic drinks consumed per day in a dose-dependent fashion. The combined use of alcohol and tobacco increases the risk for oral cancer far greater than either independently. Alcohol use has been shown to be an independent risk factor for development of oral premalignant lesions (leukoplakia or erythroplakia), which can progress to cancer.
Human papillomavirus (HPV) infection
There is an association between HPV and oral cancer, particularly HPV type 16 as shown in multiple case-control studies.[16,17,18,19,20,21,22] HPV 16 accounts for 90% to 95% of HPV-positive oropharyngeal tumors, but other high-risk subtypes include 18, 31, 33, and 35. The mechanism of HPV in the etiology of oral cancers may be related to its oncoproteins E6 and E7, which bind to and trigger the degradation of the p53 and pRB tumor suppressor proteins, respectively. HPV accounts for a relatively small proportion of oropharyngeal cancers compared to tobacco and alcohol. However, the rates of HPV-associated oropharyngeal cancers appear to be increasing.[20,23]
Carcinoma of the lip, predominantly on the lower lip, occurs in approximately 3,600 persons per year. Epidemiologically, these tumors behave akin to squamous cell carcinoma of the skin, and most are related to sun exposure, although chronic direct exposure to tobacco (i.e., the location where a pipe or cigarette is habitually held) is also associated with an increased risk of carcinoma of the lip.[24,25,26] Men have a higher risk of lip cancer than women. This has been attributed to tobacco use, greater occupational exposure to sunlight among men, and possibly due to the shielding effect of lipstick in women.
Avoidance and cessation of tobacco use
The cessation of cigarette smoking is associated with a 50% reduction of risk of developing oral cancer within 3 to 5 years  and a return to a normal level of risk for development of oral cancer within 10 years. Dentists and other health professionals can play an integral role in smoking cessation advice and encouragement.
Dentists can also participate in the full scope of pharmacological and behavioral interventions for smoking cessation. A study has shown that only 25% of tobacco users report receiving advice to quit tobacco use from their dentist, a proportion less than that received from their physician. There was a dramatic increase in the use of cigars of about 250% during the period between 1993 and 1998  and heavy cigar use is particularly associated with oral cancer development.
Interventions With Inadequate Evidence as to Whether They Reduce Risk of Oral Cancer
Alcohol avoidance and cessation
Because alcohol is associated with oral cancer in a dose-dependent fashion,[9,11,31,32] it is believed that cessation or avoidance of alcohol would result in a lower incidence of oral cancer. The evidence is inadequate, however, of reduced oral cancer among people who have stopped consuming alcohol.
Association with HPV 16–positive squamous cell carcinoma of the head and neck (SCCHN) is independently associated with several measures of sexual behavior, including number of self-reported oral sex partners, and exposure to marijuana, but not with cumulative measures of the usual risk factors of tobacco smoking, alcohol drinking, and poor oral hygiene.[16,33] Additionally, marijuana use may interact with high-risk HPV infection to promote SCCHN. Direct evidence is not available to determine if restricting these exposures will impact overall incidence or outcome of oral cancer.
Dietary changes and dietary supplements
Several studies have shown an inverse association of fruit intake and the development of oral cancer, particularly in those who use tobacco.[9,31,34,35,36] Fiber, in the form of vegetable intake, has similarly been shown to be associated with a decreased risk of oral cancer. It is estimated that intake of fruits and vegetables may lower the risk of development of oral cancer by 30% to 50%.[34,37] The evidence is inadequate, however, of reduced oral cancer among people who have made changes in their diet.
Dietary supplementation with alpha-tocopherol acetate (vitamin E) 50 mg per day and beta carotene 20 mg per day has been tested in a large randomized placebo-controlled 2 × 2 factorial trial of 29,133 male smokers aged 50 to 69 years. After a median follow-up of 6.1 years, there were a total of 65 incident oropharyngeal cancers, with no statistically significant differences between the placebo and the active agents, whether alone or in combination. Moreover, in the same trial, beta carotene was associated with increased lung cancer incidence and mortality.
The majority of cases of carcinoma of the lip occur on the lower lip, which has greater sun exposure than the upper lip. While tobacco has been strongly associated with lip cancer, sun exposure may be a factor as well. Sunscreen use has been associated with a lower incidence of skin cancers [39,40] and thus may lower the incidence of lip cancer. In a study of women in Los Angeles, a decreased risk of lip cancer was found to be associated with the daily use of lip protection (mostly colored lipstick). Lip balm with sun protection is widely available.
Agents for the reversal or prevention of recurrence of oral lesions that sometimes progress to cancer have been evaluated, with equivocal results. A randomized controlled trial (RCT)  found a protective effect of fenretinide against development of relapsed and new leukoplakias during 1 year of fenretinide treatment. The study had insufficient power to determine the effect on oral cancer incidence due to premature closure of the study. Other agents have been investigated for treatment of oral premalignant lesions.[42,43,44,45,46,47] None have been proven to prevent progression to oral malignancy, and none can be considered part of standard care.
A systematic Cochrane group literature review summarized randomized trials of either surgical (excision, laser ablation, or cryotherapy) or nonsurgical interventions for the treatment of oral leukoplakia. Despite the fact that surgery is the most common therapy for oral leukoplakia, there were no studies of this modality with untreated controls for comparison. Nine randomized trials of medical interventions met inclusion criteria, and only two were judged to have a low risk of study bias. Only two (studying topical bleomycin, oral vitamin A, or oral beta carotene) reported malignant transformation as an endpoint, and neither showed a difference between the active treatment and control study groups. All of the studies had short follow-up relative to the natural progression rate of leukoplakia; the mean follow-up was no longer than 15 months. Although intermediate endpoints, such as clinical response, were reported in seven of the trials, none of these endpoints has been validated as predictive of malignant transformation.
Several agents have been studied for the prevention of second cancers in patients previously treated for SCCHN, including oropharyngeal cancer. High-dose isotretinoin (50–100 mg/m² orally per day for 12 months) was compared to placebo in a small study of 103 such patients.[49,50] Overall survival and incidence of recurrence of the primary tumors were similar in both treatment groups. There was a statistically significant decrease in rate of second head and neck cancers in the isotretinoin group, but isotretinoin toxicity was substantial, making the use of this agent impractical at these doses. To mitigate this toxicity, low-dose isotretinoin (30 mg orally per day for 3 years) was subsequently tested in a placebo-controlled randomized trial of 1,190 patients with head and neck cancer, but there was no decrease in incidence of second primary tumors at this dose. Likewise, vitamin A and N-acetylcysteine, as well as alpha-tocopherol and beta carotene, have shown no efficacy in RCTs for the prevention of second primary tumors of the oropharynx in patients who had been treated for either head and neck cancer or lung cancer.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Description of the Evidence
Updated statistics with estimated new cases and deaths for 2012 (cited American Cancer Society as reference 2).
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about oral cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Oral Cancer Prevention. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/prevention/oral/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2012-01-26
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