Oral Cavity and Nasopharyngeal Cancers Screening (PDQ®)–Health Professional Version

Benefits

There is inadequate evidence to establish whether screening would result in a decrease in mortality from oral cavity and nasopharyngeal cancers.

Magnitude of Effect: No evidence of benefit, and harms have not been quantified.

Harms

Harms, although unavoidable, have not been quantified on the basis of the literature. However, there are some unavoidable harms that would be associated with routine screening, including:

Magnitude of Effect: Unknown.

Epstein-Barr Virus (EBV) Infection

Based on solid evidence, EBV infection causes nasopharyngeal cancer in high-incidence areas.[1] Collective evidence includes numerous case-control studies and cohort studies that show a higher proportion of patients with nasopharyngeal cancer who have anti-EBV antibodies than controls and that seropositive status precedes tumor diagnosis.[2,3] Recent studies have also found circulating cell-free EBV DNA in patients with nasopharyngeal cancer but not in controls.[4] EBV alone is not a sufficient cause because 90% of adults worldwide are infected with the virus, but only a small proportion develop nasopharyngeal cancer.[5] EBV infection is subclinical and occurs early in childhood. The pathogenesis is thought to involve the virus establishing latency in epithelial cells that have already undergone premalignant genetic changes.

One of the first studies to show an association was a cohort study that found higher anti-EBV titers in 84% of the 235 East African and Chinese patients with nasopharyngeal carcinoma.[2,5] The same study found higher anti-EBV titers with higher-stage tumor, and a case-control component of the study revealed that high anti-EBV titers were six times more likely in patients with nasopharyngeal carcinoma than in patients with head and neck cancers at other sites.

Other studies show elevation in both IgG and IgA antibody titers to EBV viral capsid antigen and other latent viral antigens, which precede tumor development by several years and are correlated with tumor burden, remission, and recurrence.[2,3] A large cohort study with 9,699 men measured both IgA antibodies against EBV capsid antigen and neutralizing antibodies against EBV-specific DNase and followed them for a later diagnosis of nasopharyngeal cancer.[3] The relative risk of nasopharyngeal carcinoma was 32.8 for individuals with both antibody markers (95% confidence interval [CI], 7.3–147.2; P < .001), and 4.0 for individuals with one marker (95% CI, 1.6–10.2; P = .003), compared with individuals with neither marker. There was a temporal relationship in that the difference in cumulative incidence between seropositive and seronegative patients increased with a longer duration of follow-up. Another study found circulating cell-free EBV DNA in 95% of patients with advanced nasopharyngeal cancer but not in controls or cured patients.[4]

Screening for Oral Cavity Cancers

There are different methods of screening for oral cavity cancers. Oral cavity cancers occur 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. Of note, 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.[3] 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.[3] An oral examination often includes looking for leukoplakia and erythroplakia lesions, which can progress to cancer.[4,5] 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.[6] 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.[7]

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 (RCTs) in any Western or other low-risk populations.[5,8-11]

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 between 1996 and 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.[12-15]

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 methodological 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.

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.[5,16] In an 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.[17] 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 biopsy confirmation was used as the gold standard outcome.[18] In part, this range of findings can be attributed to varying study populations, sample size and settings, and criteria for positive-clinical examinations and for scoring a biopsy as positive.

Screening for Nasopharyngeal Cancer

Serum Epstein-Barr virus (EBV)–associated antibodies and circulating cell-free EBV DNA testing have been used for nasopharyngeal cancer diagnosis and screening. In an observational study of 20,349 men aged 40 to 62 years, circulating cell-free EBV DNA testing was used to screen for nasopharyngeal cancer.[19,20] A total of 1.5% of participants tested positive twice for EBV DNA and had further workup, leading to a diagnosis of nasopharyngeal cancer for 34 patients. The EBV DNA test had a sensitivity of 97.1% (95% CI, 95.5%–98.7%) and specificity of 98.6% (95% CI, 98.6%–98.7%). Without a control group, the study compared stage of disease at diagnosis with a historical cohort and found a higher proportion of stage I and stage II disease (71% vs. 20%; P < .001) and superior 3-year progression-free survival in the screen-detected population. However, the survival benefit in the study may also be caused by lead-time bias.

Other screening programs in southern China use EBV-associated antibodies, but their effects are difficult to determine because of lack of controls for comparison of survival outcomes.[20-22] In summary, current screening studies for nasopharyngeal cancer do not provide solid evidence of a benefit associated with screening for nasopharyngeal cancer, especially in nonendemic regions such as the United States.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about oral cavity and nasopharyngeal cancers screening. It is intended as a resource to inform and assist clinicians in the care of their 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).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

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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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The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Oral Cavity and Nasopharyngeal Cancers Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/head-and-neck/hp/oral-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389219]

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