Description of the Evidence
Incidence and mortality
An estimated 41,380 new cases of oral cancer will be diagnosed in the United States in 2013, and an estimated 7,890 people will die of the disease. This form of cancer accounts for about 3% of cancers in men. The overall annual incidence in the United States is about 10.8 per 100,000 men and women; the median age at diagnosis of oral cavity or pharyngeal cancer was 62 years from 2005 to 2009.
Incidence has been falling in men since 1975 and in women since 1980. However, incidence has recently been increasing for oral cancers related to human papillomavirus (HPV) infection. About 60% of oral/pharyngeal cancers are moderately advanced (regional stage) or metastatic at the time of diagnosis.
The estimated annual worldwide number of incident oral cancers is about 275,000, with an approximately 20-fold variation geographically. South and Southeast Asia (India, Sri Lanka, Pakistan, and Bangladesh), France, and Brazil have particularly high rates. In most countries, men have higher rates of oral cancer than women (due to tobacco use) and higher rates of lip cancer (due to sunlight exposure from outdoor occupations).Risk factors
The primary risk factors for oral cancer in American men and women are tobacco (including smokeless tobacco) and alcohol use. Infection with HPV-16 has been associated with an excess risk of developing squamous cell carcinoma of the oropharynx.Evidence of Benefit Associated With Screening
No population-based screening programs for oral cancers have been implemented in developed countries, although opportunistic screening or screening as part of a periodic health examination has been advocated.[5,6] There are different methods of screening for oral cancers. Oral cancer occurs in a region of the body that is generally accessible to physical examination by the patient, the dentist, and the physician; and visual examination is the most common method used to detect visible lesions. Other methods have been used to augment clinical detection of oral lesions and include toluidine blue, brush biopsy, and fluorescence staining.
An inspection of the oral cavity is often part of a physical examination in a dentist's or physician's office. It has been pointed out that high-risk individuals visit their medical doctors more frequently than they visit their dentists. Although physicians are more likely to provide risk-factor counseling (such as tobacco cessation), they are less likely than dentists to perform an oral cancer examination. Overall, only a fraction (~20%) of Americans receive an oral cancer examination. Black patients, Hispanic patients, and those who have a lower level of education are less likely to have such an examination, perhaps because they lack access to medical care. An oral examination often includes looking for leukoplakia and erythroplakia lesions, which can progress to cancer.[8,9] One study has shown that direct fluorescence visualization (using a simple hand-held device in the operating room) could identify subclinical high-risk fields with cancerous or precancerous changes extending up to 25 mm beyond the primary tumor in 19 of 20 patients undergoing oral surgery for invasive or in situ squamous cell tumors. However, this finding has not yet been tested in a screening setting. Data suggest that molecular markers may be useful in the prognosis of these premalignant oral lesions.
The routine examination of asymptomatic and symptomatic patients can lead to detection of earlier stage cancers and premalignant lesions. There is no definitive evidence, however, to show that this screening can reduce oral cancer mortality, and there are no randomized controlled trials (RCT) in any Western or other low-risk populations.[9,12-15]
In a single RCT of screening versus usual care, 13 geographic clusters in the Trivandrum district of Kerala, India, were randomly assigned to receive systematic oral visual screening by trained health workers (seven screened clusters, six control clusters) every 3 years for four screening rounds during the period 1996 to 2008. During a 15-year follow-up period, there were 138 deaths from oral cancer in the screening group with a cause–specific mortality rate of 15.4 per 100,000 person-years, and 154 deaths in the control group with a mortality rate of 17.1 per 100,000 person-years (relative risk [RR] = 0.88; 95% confidence interval [CI], 0.69–1.12). In a subset analysis restricted to tobacco or alcohol users, the mortality rates were 30 and 39 per 100,000 person-years, respectively (RR = 0.76; 95% CI, 0.60–0.97). There was no apparent adjustment of the CIs for the cluster design. In another subgroup analysis, mortality hazard ratios were calculated for groups defined by number of times screened, but the inappropriate comparison in each case was to the control group of the whole study. No data on treatment of oral cancers were presented.[16-19]
Aside from the issues of generalizability to other populations and lack of an overall statistically significant result in cause-specific mortality, interpretation of the results is made difficult by serious lacks in methodologic detail about the randomization process, allocation concealment, adjustment for clustering effect, and information about treatment. The total number of clusters randomized was small, and there were different distributions of income and household possessions between the two study arms. Withdrawals and dropouts were not clearly described. In summary, the sole randomized trial does not provide solid evidence of a cause-specific mortality benefit associated with systematic oral cavity visual examination.Adjunctive techniques to visual examination
Techniques such as toluidine blue staining, brush biopsy/cytology, or fluorescence imaging as the primary screening tool or as an adjunct for screening have not been shown to have superior sensitivity and specificity for visual examination alone or to yield better health outcomes.[9,20] In a RCT conducted in Keelung County, Taiwan, 7,975 individuals at high risk of oral cancer due to cigarette smoking or betel quid chewing were randomly assigned to receive a one-time oral cancer examination after gargling with toluidine blue or a blue placebo dye. The positive test rates were 9.5% versus 8.3%, respectively, (P = .047). The detection of premalignant lesions was not statistically different (rate ratio = 1.05; 95% CI, 0.74–1.41). The number of overall oral cancers diagnosed within the short follow-up period of 5 years was too small for valid comparison (six in each group).
The operating characteristics of the various techniques used as an adjunct to oral visual examination are not well established. A systematic literature review of toluidine blue, a variety of other visualization adjuncts, and cytopathology in the screening setting revealed a very broad range of reported sensitivities, specificities, and positive predictive values when using biopsy confirmation as the gold standard outcome. In part, this was due to varying study populations, sample size and settings, as well as criteria for positive-clinical examinations and for scoring a biopsy as positive.Evidence of Harm Associated With Screening
Harms associated with screening for oral cancer are poorly studied in any quantifiable way. However, there are some unavoidable harms that would be associated with routine screening, including:
- Detection of cases that are already incurable, leading to increased morbidity.
- Unnecessary treatment of lesions that would not have progressed (overdiagnosis).
- Psychologic consequences of false-positive tests.
An additional potential harm is misdiagnosis and resulting under- or over-treatment, given the subjective pathology judgments in reading biopsies of oral lesions. When 87 biopsy diagnoses of oral lesions were compared between 21 local pathologists and double-reading by two of three central pathologists in a multicenter study of patients with prior upper aerodigestive tract cancers, agreement was only fair-to-good (kappa weighted-statistic = 0.59; 95% CI, 0.45–0.72). In a bivariate categorization of carcinoma in situ plus carcinoma versus less serious lesions, the agreement was poor, but with very wide CIs (kappa-statistic = 0.39; 95% CI, -0.12–0.97). The investigators in the same study analyzed an agreement between the local and central pathologists on clinically normal tissue adjacent to 67 biopsied clinically-suspicious lesions. The agreement on clinically normal tissue was better than for visibly abnormal lesions, but still not in the excellent range (kappa weighted-statistic = 0.75; 95% CI, 0.64–0.86).References
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