Description of the Evidence
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 2007–2011) 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 45,780 new cases of oral cancer diagnosed in the United States in 2015 and 8,650 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.)
Factors associated with increased risk of oral cancer
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.[12-15] 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.[17-23] HPV 16 accounts for 90% to 95% of HPV-positive oropharyngeal cancer (HPV-OPC), but other high-risk subtypes include 18, 31, 33, and 35. Among patients with HPV-OPC, there is no evidence of increased oral HPV infection in their sexual partners compared with the general population prevalence. 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 with tobacco and alcohol. However, the rates of HPV-associated oropharyngeal cancers appear to be increasing.[21,25]
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.[26-28] 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.
Interventions Associated With a Decreased Risk of Oral Cancer
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,[10,12,33,34] 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.
Avoidance of HPV infection
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.[17,35] Additionally, marijuana use may interact with high-risk HPV infection to promote SCCHN. Direct evidence is not available to determine whether 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.[10,33,36-38] 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%.[36,39] 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.
Sun avoidance and sunscreen use
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 [41,42] 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.[44-49] 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. Although 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 with placebo in a small study of 103 such patients.[51,52] 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.
- Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2011. Bethesda, Md: National Cancer Institute, 2014. Also available online. Last accessed February 6, 2015.
- American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online. Last accessed January 7, 2015.
- Ferlay J, Shin HR, Bray F, et al.: GLOBOCAN 2008: Cancer Incidence and Mortality Worldwide in 2008. Lyon, France: IARC CancerBase No. 10. Available online. Last accessed January 9, 2015.
- Parkin DM, Bray F, Ferlay J, et al.: Global cancer statistics, 2002. CA Cancer J Clin 55 (2): 74-108, 2005 Mar-Apr. [PUBMED Abstract]
- Noonan VL, Kabani S: Diagnosis and management of suspicious lesions of the oral cavity. Otolaryngol Clin North Am 38 (1): 21-35, vii, 2005. [PUBMED Abstract]
- Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2008. Bethesda, Md: National Cancer Institute, 2011. Also available online. Last accessed February 6, 2015.
- Reducing the Health Consequences of Smoking: 25 Years of Progress - a Report of the Surgeon General. Rockville, Md : U.S. Dept. 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, 1989.
- Cinciripini PM, McClure JB: Smoking cessation: recent developments in behavioral and pharmacologic interventions. Oncology (Huntingt) 12 (2): 249-56, 259; discussion 260, 265, 2, 1998. [PUBMED Abstract]
- Spitz MR, Newell GR: Descriptive epidemiology of squamous cell carcinoma of the upper aerodigestive tract. Cancer Bull 39(2): 79-81, 1987.
- Macfarlane GJ, Zheng T, Marshall JR, et al.: Alcohol, tobacco, diet and the risk of oral cancer: a pooled analysis of three case-control studies. Eur J Cancer B Oral Oncol 31B (3): 181-7, 1995. [PUBMED Abstract]
- Firth NA: Marijuana use and oral cancer: a review. Oral Oncol 33 (6): 398-401, 1997. [PUBMED Abstract]
- Blot WJ, McLaughlin JK, Winn DM, et al.: Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 48 (11): 3282-7, 1988. [PUBMED Abstract]
- Altieri A, Bosetti C, Gallus S, et al.: Wine, beer and spirits and risk of oral and pharyngeal cancer: a case-control study from Italy and Switzerland. Oral Oncol 40 (9): 904-9, 2004. [PUBMED Abstract]
- Talamini R, La Vecchia C, Levi F, et al.: Cancer of the oral cavity and pharynx in nonsmokers who drink alcohol and in nondrinkers who smoke tobacco. J Natl Cancer Inst 90 (24): 1901-3, 1998. [PUBMED Abstract]
- Talamini R, Franceschi S, Barra S, et al.: The role of alcohol in oral and pharyngeal cancer in non-smokers, and of tobacco in non-drinkers. Int J Cancer 46 (3): 391-3, 1990. [PUBMED Abstract]
- Hashibe M, Sankaranarayanan R, Thomas G, et al.: Alcohol drinking, body mass index and the risk of oral leukoplakia in an Indian population. Int J Cancer 88 (1): 129-34, 2000. [PUBMED Abstract]
- Schwartz SM, Daling JR, Doody DR, et al.: Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst 90 (21): 1626-36, 1998. [PUBMED Abstract]
- Mork J, Lie AK, Glattre E, et al.: Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344 (15): 1125-31, 2001. [PUBMED Abstract]
- D'Souza G, Kreimer AR, Viscidi R, et al.: Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356 (19): 1944-56, 2007. [PUBMED Abstract]
- Franceschi S, Muñoz N, Bosch XF, et al.: Human papillomavirus and cancers of the upper aerodigestive tract: a review of epidemiological and experimental evidence. Cancer Epidemiol Biomarkers Prev 5 (7): 567-75, 1996. [PUBMED Abstract]
- Marklund L, Hammarstedt L: Impact of HPV in Oropharyngeal Cancer. J Oncol 2011: 509036, 2011. [PUBMED Abstract]
- Gillison ML, Koch WM, Capone RB, et al.: Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92 (9): 709-20, 2000. [PUBMED Abstract]
- Smith EM, Ritchie JM, Summersgill KF, et al.: Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst 96 (6): 449-55, 2004. [PUBMED Abstract]
- D'Souza G, Gross ND, Pai SI, et al.: Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners. J Clin Oncol 32 (23): 2408-15, 2014. [PUBMED Abstract]
- Ramqvist T, Dalianis T: An epidemic of oropharyngeal squamous cell carcinoma (OSCC) due to human papillomavirus (HPV) infection and aspects of treatment and prevention. Anticancer Res 31 (5): 1515-9, 2011. [PUBMED Abstract]
- Pogoda JM, Preston-Martin S: Solar radiation, lip protection, and lip cancer risk in Los Angeles County women (California, United States). Cancer Causes Control 7 (4): 458-63, 1996. [PUBMED Abstract]
- Silverman S Jr, ed.: Oral Cancer. 4th ed. Hamilton, Canada: BC Decker, 1998.
- Perea-Milla López E, Miñarro-Del Moral RM, Martínez-García C, et al.: Lifestyles, environmental and phenotypic factors associated with lip cancer: a case-control study in southern Spain. Br J Cancer 88 (11): 1702-7, 2003. [PUBMED Abstract]
- Samet JM: The health benefits of smoking cessation. Med Clin North Am 76 (2): 399-414, 1992. [PUBMED Abstract]
- Mecklenburg RE, Christen AG, et al.: How to Help Your Patients Stop Using Tobacco: a National Cancer Institute Manual for the Oral Health Team. Bethesda, Md: National Institutes of Health, National Cancer Institute, 1993.
- Martin LM, Bouquot JE, Wingo PA, et al.: Cancer prevention in the dental practice: oral cancer screening and tobacco cessation advice. J Public Health Dent 56 (6): 336-40, 1996 Fall. [PUBMED Abstract]
- Nelson NJ: "Big Smoke" has big risks: daily cigar use causes cancer, heart disease. J Natl Cancer Inst 90 (8): 562-4, 1998. [PUBMED Abstract]
- La Vecchia C, Tavani A, Franceschi S, et al.: Epidemiology and prevention of oral cancer. Oral Oncol 33 (5): 302-12, 1997. [PUBMED Abstract]
- Bagnardi V, Blangiardo M, La Vecchia C, et al.: Alcohol consumption and the risk of cancer: a meta-analysis. Alcohol Res Health 25 (4): 263-70, 2001. [PUBMED Abstract]
- Gillison ML, D'Souza G, Westra W, et al.: Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 100 (6): 407-20, 2008. [PUBMED Abstract]
- Winn DM, Ziegler RG, Pickle LW, et al.: Diet in the etiology of oral and pharyngeal cancer among women from the southern United States. Cancer Res 44 (3): 1216-22, 1984. [PUBMED Abstract]
- Winn DM: Diet and nutrition in the etiology of oral cancer. Am J Clin Nutr 61 (2): 437S-445S, 1995. [PUBMED Abstract]
- Horn-Ross PL, Morrow M, Ljung BM: Diet and the risk of salivary gland cancer. Am J Epidemiol 146 (2): 171-6, 1997. [PUBMED Abstract]
- Morse DE, Pendrys DG, Katz RV, et al.: Food group intake and the risk of oral epithelial dysplasia in a United States population. Cancer Causes Control 11 (8): 713-20, 2000. [PUBMED Abstract]
- Wright ME, Virtamo J, Hartman AM, et al.: Effects of alpha-tocopherol and beta-carotene supplementation on upper aerodigestive tract cancers in a large, randomized controlled trial. Cancer 109 (5): 891-8, 2007. [PUBMED Abstract]
- Naylor MF, Farmer KC: The case for sunscreens. A review of their use in preventing actinic damage and neoplasia. Arch Dermatol 133 (9): 1146-54, 1997. [PUBMED Abstract]
- Cummings SR, Tripp MK, Herrmann NB: Approaches to the prevention and control of skin cancer. Cancer Metastasis Rev 16 (3-4): 309-27, 1997 Sep-Dec. [PUBMED Abstract]
- Chiesa F, Tradati N, Grigolato R, et al.: Randomized trial of fenretinide (4-HPR) to prevent recurrences, new localizations and carcinomas in patients operated on for oral leukoplakia: long-term results. Int J Cancer 115 (4): 625-9, 2005. [PUBMED Abstract]
- Halder A, Raychowdhury R, Ghosh A, et al.: Black tea (Camellia sinensis) as a chemopreventive agent in oral precancerous lesions. J Environ Pathol Toxicol Oncol 24 (2): 141-4, 2005. [PUBMED Abstract]
- Lin DT, Subbaramaiah K, Shah JP, et al.: Cyclooxygenase-2: a novel molecular target for the prevention and treatment of head and neck cancer. Head Neck 24 (8): 792-9, 2002. [PUBMED Abstract]
- Armstrong WB, Kennedy AR, Wan XS, et al.: Clinical modulation of oral leukoplakia and protease activity by Bowman-Birk inhibitor concentrate in a phase IIa chemoprevention trial. Clin Cancer Res 6 (12): 4684-91, 2000. [PUBMED Abstract]
- Rudin CM, Cohen EE, Papadimitrakopoulou VA, et al.: An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia. J Clin Oncol 21 (24): 4546-52, 2003. [PUBMED Abstract]
- Papadimitrakopoulou VA, Lee JJ, William WN Jr, et al.: Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy. J Clin Oncol 27 (4): 599-604, 2009. [PUBMED Abstract]
- Tsao AS, Liu D, Martin J, et al.: Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila) 2 (11): 931-41, 2009. [PUBMED Abstract]
- Lodi G, Sardella A, Bez C, et al.: Interventions for treating oral leukoplakia. Cochrane Database Syst Rev (4): CD001829, 2006. [PUBMED Abstract]
- Hong WK, Lippman SM, Itri LM, et al.: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323 (12): 795-801, 1990. [PUBMED Abstract]
- Benner SE, Pajak TF, Lippman SM, et al.: Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: long-term follow-up. J Natl Cancer Inst 86 (2): 140-1, 1994. [PUBMED Abstract]
- Khuri FR, Lee JJ, Lippman SM, et al.: Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst 98 (7): 441-50, 2006. [PUBMED Abstract]
- van Zandwijk N, Dalesio O, Pastorino U, et al.: EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 92 (12): 977-86, 2000. [PUBMED Abstract]
- Bairati I, Meyer F, Gélinas M, et al.: A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients. J Natl Cancer Inst 97 (7): 481-8, 2005. [PUBMED Abstract]