Description of the Evidence
Incidence and mortality
An estimated 42,440 new cases of oral cancer will be diagnosed in the United States in 2014, and an estimated 8,390 people will die of the disease. This form of cancer accounts for about 4% 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.
From 2006 to 2010, incidence rates were stable in men but decreased in women by 0.9% per year. 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).
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).
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- Warnakulasuriya S: Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 45 (4-5): 309-16, 2009 Apr-May. [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]
- Opportunistic oral cancer screening: a management strategy for dental practice. BDA Occasional Paper 6: 1-36, 2000. Also available online. Last accessed February 21, 2014.
- Smith RA, Cokkinides V, Brooks D, et al.: Cancer screening in the United States, 2011: A review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 61 (1): 8-30, 2011 Jan-Feb. [PUBMED Abstract]
- Kerr AR, Changrani JG, Gany FM, et al.: An academic dental center grapples with oral cancer disparities: current collaboration and future opportunities. J Dent Educ 68 (5): 531-41, 2004. [PUBMED Abstract]
- Warnakulasuriya S, Johnson NW, van der Waal I: Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 36 (10): 575-80, 2007. [PUBMED Abstract]
- Brocklehurst P, Kujan O, Glenny AM, et al.: Screening programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev (11): CD004150, 2010. [PUBMED Abstract]
- Poh CF, Zhang L, Anderson DW, et al.: Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients. Clin Cancer Res 12 (22): 6716-22, 2006. [PUBMED Abstract]
- Poh CF, Zhang L, Lam WL, et al.: A high frequency of allelic loss in oral verrucous lesions may explain malignant risk. Lab Invest 81 (4): 629-34, 2001. [PUBMED Abstract]
- Screening for oral cancer. In: Fisher M, Eckhart C, eds.: Guide to Clinical Preventive Services: an Assessment of the Effectiveness of 169 Interventions. Report of the U.S. Preventive Services Task Force. Baltimore, Md: Williams & Wilkins, 1989, pp 91-94.
- Antunes JL, Biazevic MG, de Araujo ME, et al.: Trends and spatial distribution of oral cancer mortality in São Paulo, Brazil, 1980-1998. Oral Oncol 37 (4): 345-50, 2001. [PUBMED Abstract]
- U.S. Preventive Services Task Force: Screening for Oral Cancer: Recommendation Statement. Rockville, Md: U.S. Preventive Services Task Force, 2004. Available online. Last accessed February 21, 2014.
- Scattoloni J: Screening for Oral Cancer: Brief Evidence Update. Rockville, Md: U.S. Preventive Services Task Force, 2004. Available online. Last accessed February 21, 2014.
- Sankaranarayanan R, Mathew B, Jacob BJ, et al.: Early findings from a community-based, cluster-randomized, controlled oral cancer screening trial in Kerala, India. The Trivandrum Oral Cancer Screening Study Group. Cancer 88 (3): 664-73, 2000. [PUBMED Abstract]
- Ramadas K, Sankaranarayanan R, Jacob BJ, et al.: Interim results from a cluster randomized controlled oral cancer screening trial in Kerala, India. Oral Oncol 39 (6): 580-8, 2003. [PUBMED Abstract]
- Sankaranarayanan R, Ramadas K, Thomas G, et al.: Effect of screening on oral cancer mortality in Kerala, India: a cluster-randomised controlled trial. Lancet 365 (9475): 1927-33, 2005 Jun 4-10. [PUBMED Abstract]
- Sankaranarayanan R, Ramadas K, Thara S, et al.: Long term effect of visual screening on oral cancer incidence and mortality in a randomized trial in Kerala, India. Oral Oncol 49 (4): 314-21, 2013. [PUBMED Abstract]
- Lingen MW, Kalmar JR, Karrison T, et al.: Critical evaluation of diagnostic aids for the detection of oral cancer. Oral Oncol 44 (1): 10-22, 2008. [PUBMED Abstract]
- Su WW, Yen AM, Chiu SY, et al.: A community-based RCT for oral cancer screening with toluidine blue. J Dent Res 89 (9): 933-7, 2010. [PUBMED Abstract]
- Patton LL, Epstein JB, Kerr AR: Adjunctive techniques for oral cancer examination and lesion diagnosis: a systematic review of the literature. J Am Dent Assoc 139 (7): 896-905; quiz 993-4, 2008. [PUBMED Abstract]
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- Fischer DJ, Epstein JB, Morton TH, et al.: Interobserver reliability in the histopathologic diagnosis of oral pre-malignant and malignant lesions. J Oral Pathol Med 33 (2): 65-70, 2004. [PUBMED Abstract]
- Fischer DJ, Epstein JB, Morton TH Jr, et al.: Reliability of histologic diagnosis of clinically normal intraoral tissue adjacent to clinically suspicious lesions in former upper aerodigestive tract cancer patients. Oral Oncol 41 (5): 489-96, 2005. [PUBMED Abstract]