Target condition being diagnosed

The target conditions of interest are oral cavity cancer and potentially malignant disorders (PMD) of the lip and oral cavity. PMD is a term used to describe a range of lesions that present in the mouth and have the potential for malignant transformation. These include: erythroplakia, non‐homogeneous leukoplakia, erosive lichen planus, oral submucous fibrosis and actinic keratosis (van der Waal 2009; Warnakulasuriya 2007).

The natural history of oral cancer is not fully understood (Napier 2008; Scully 2009). Carcinogenesis is a complex disease process; not all oral cancers will be preceded by PMD and not all PMD undergoes malignant transformation. Erythroplakia, non‐homogeneous leukoplakia, erosive lichen planus, oral submucous fibrosis and actinic keratosis are the most important PMDs (Warnakulasuriya 2007) to proceed to carcinoma. Oral leukoplakia is the most common form of PMD and is defined as "white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer" (Warnakulasuriya 2007). Between < 1% and 18% of oral leukoplakias undergo malignant transformation. The presence of epithelial dysplasia can help predict malignant development in oral leukoplakia but the process is not linear; some mild dysplastic lesions undergo malignant transformation, whilst some severe lesions resolve (Jaber 2003; Reibel 2003). Carcinoma can also develop from lesions in which epithelial dysplasia was not previously diagnosed (Jaber 2003; Reibel 2003). As a result, most authorities regard leukoplakia as a dynamic rather than a static process (Napier 2008). In contrast, PMDs that are red or predominantly red in colour (e.g. erythroplakia and erythroleukoplakias) undergo malignant transformation more readily (Mashberg 1988; Mashberg 1995; Scully 2009).

Estimates of malignant transformation rates (MTR) vary enormously, from site to site within the mouth, from population to population and from study to study (Napier 2008). The MTR of hospital‐based surveys are consistently higher than community‐based studies because of sampling bias. Petti 2003 calculated a global MTR of oral leukoplakia of 1.36% per year (95% confidence interval (CI) 0.69% to 2.03%) based on the prevalence of oral leukoplakia, but this far exceeds the numbers of actual cases of malignancy. Virtually all studies emphasize the chronicity of oral PMD, with an increasing tendency to malignant change in the first five years. For example, the incidence of oral squamous cell carcinoma (OSCC) arising from leukoplakia in Californians was greatest in the second year of follow‐up (11 out of 45; 24%) (Silverman 1984). The proportion of PMD that will develop OSCC is uncertain but low; best estimates suggest a rate of less than 2% per annum (Napier 2008).

The early detection and management of potentially malignant disorders of the lip and oral cavity that require intervention may reduce malignant transformations (though will not totally eliminate malignancy occurring), or if malignancy is detected during surveillance, there is some evidence that appropriate treatment may improve survival rates (Brocklehurst 2010; van der Waal 2009; Warnakulasuriya 2007). However, Lodi 2006 investigated the effectiveness of different management strategies for oral leukoplakia and found a lack of evidence for surgical interventions, including laser therapy and cryotherapy. Vitamin A, retinoids, beta carotene, carotenoids, bleomycin, mixed tea and ketorolac have also been tried, but none of the treatments tested showed a benefit when compared with the placebo. Lodi et al concluded that there was no evidence of effective treatment in preventing the malignant transformation of leukoplakia (Lodi 2006). There is also debate in the literature about the impact "field change" (Holmstrup 2006; Holmstrup 2009). Holmstrup argues that even if early lesions are surgically removed, the risk of malignant change can remain as a result of the lesion representing a small area of a wider field of damaged mucosa (Holmstrup 2006; Holmstrup 2009).

Technologies to treat and manage oral cancer have progressed substantially, as shown by systematic reviews of randomised controlled trials of interventions (e.g. Bessell 2011; Furness 2011; Glenny 2010). Once frank malignancy has been detected, the traditional management of oral cancer is through surgery and radiotherapy. More recently, systemic chemotherapy has been included as part of the treatment regimen before or during radiotherapy. Surgery for the treatment of oral cancer is followed by exacting reconstructive surgery to restore form and function. Debilitating side effects can occur as a result of both the surgery and radiotherapy and chemotherapy, adversely affecting an individual's quality of life. The five‐year survival following diagnosis has remained at around 50% for the past 30 years in most countries (Parkin 2001; Warnakulasuriya 2009). Recent US data show a statistically significant improvement among patients treated for oral squamous cell carcinoma from 55% in 1984 to 1986 to 60% in the 1996 to 2003 time frame (Jemal 2008). This is in marked contrast to the improved survival rates in many other cancers, such as those of the breast and the colon (Cancer Research UK), but may be explained at least in some part by the fact that oral cancer is more often diagnosed at a late stage of the disease, when prognosis is poorer and the risks of significant morbidity and mortality are substantially higher (Rogers 2009; Rusthoven 2010).

Index test(s)

Reviews of primary studies of diagnostic test accuracy in this area have identified a number of index tests which could be used as adjuncts to the conventional visual and tactile oral examination (COE) to improve earlier detection of lip and oral cavity cancer and PMD (Fedele 2009; Leston 2010; Lingen 2008; Patton 2008; Rethman 2010). These include:

• vital rinsing or staining (Toluidine blue, Tolonium chloride)

• light‐based detection (such as ViziLite and ViziLite Plus, Microlux/DL, VELscope, Orascoptic DK, Identafi 3000)

• mouth self examination

• blood and saliva analyses.

Vital rinsing and oral cytology are long available adjuncts to a conventional oral examination (Leston 2010; Lingen 2008). Other tests such as light‐based detection systems have become commercially available only more recently. Mouth self examination is a simple technique with world wide application. Blood analysis and saliva analysis are more novel tests at an early stage of evaluation. It is worth noting that for an index test to obtain the US Food and Drug Administration (FDA) 'clearance' (the term reserved for non‐invasive devices) a demonstration of efficacy is not required, only a demonstration of safety.

Of the index tests listed above, vital rinsing, light‐based detection, mouth self examination and blood and saliva analyses could be used as screening adjuncts to the COE (Additional Table 1). Where access to general dental practitioners or general medical practitioners is limited, either as a result of geographical location or barriers to uptake of healthcare provision, screening using the index tests listed above could, in principle, be undertaken by trained healthcare workers; all have the potential to be used as adjuncts to the COE by healthcare workers or clinicians undertaking screening of the general population. Adding any one of the proposed index tests to the COE, the tests could have a triage role in detecting lesions of uncertain significance with referral where appropriate. For instance, traumatic keratoses are common, and referring each patient with a white patch to a specialist to undergo a scalpel biopsy is excessive, and incurs increased financial cost and patient worry, and potentially delays the more urgent referrals being seen. A non‐invasive index test or combination of tests adjunctive to the COE that provides a frontline clinician with a high degree of accuracy would not only reduce the number of patients with benign disease being referred, but could avoid the need for invasive biopsy in patients testing negative.

A companion Cochrane systematic review evaluates the diagnostic accuracy of index tests in individuals presenting with clinically evident lesions (Liu 2012).

Clinical pathway

The standard process of screening apparently healthy adults for PMD and cancer of the lip or oral cavity is by a systematic and thorough visual inspection of the oral mucosa and palpation of the neck under normal (incandescent) light for lymphadenopathy. In most instances this is carried out by a frontline clinician opportunistically as part of a routine recall examination by a dentist. This conventional visual and tactile oral examination (COE) used can be conducted with the minimum of effort and distress to the individual (Additional Table 1). Screening can be carried out opportunistically, for instance when an individual presents to their dentist for a check‐up, or as part of an organised screening programme. The COE is usually followed by referral for further investigation if this is deemed necessary. The form that further investigation takes is variable nationally and internationally; it could be an examination/biopsy by a specialist in oral medicine or oral surgery at a secondary or tertiary clinic.

Rationale

Oral cancer is a significant global health problem with increasing incidence and mortality rates (Ferlay 2010; Warnakulasuriya 2009). Cancer of the lip or oral cavity is a relatively common cancer worldwide, with an estimated 263,000 new cases and 127,000 deaths in 2008, and an increasing incidence in recent years (Ferlay 2010). There is wide geographic variation in disease incidence and mortality, with almost double the incidence in low‐income and middle‐income countries as in high‐income countries, and a threefold increase in mortality. Tobacco use, alcohol consumption, betel quid chewing and low socio‐economic status have traditionally been thought to be the most important risk factors of oral cancer (Conway 2008; Faggiano 1997; La Vecchia 1997; Macfarlane 1995; Ogden 2005). Men have had a higher incidence of oral cancer than women (Ferlay 2010), but this disparity can be explained by men having a higher exposure to the above risk factors (Freedman 2007). The gender difference has narrowed in recent decades from a ratio of five males to one female diagnosed with oral cancers in the 1960s to less than two to one in 2008 (Ferlay 2010). Although traditionally the risk of oral cancer increases with age, the incidence among younger adults has been increasing in the European Union and the United States (Warnakulasuriya 2009). In the United Kingdom, one in 10 cases are now below the age of 45 years (Cancer Research UK).The five‐year survival rate depends on multiple factors, including patient and tumour characteristics, treatment received and stage at diagnosis. Oral cancer incidence and mortality can be reduced using three approaches: (i) primary prevention, (ii) secondary prevention, screening and early detection, and (iii) improved treatment (Scully 2000b).

Successful early detection of oral cavity cancer or PMD is highly dependent on whether individuals with the disease present for a screen. Early detection relies on the awareness and motivation of the clinician or patient in identifying a suspicious lesion or symptom while it is still at an early stage. Whilst many organisations advocate cancer‐related checks, including the American Cancer Society for individuals of all risk groups (American Cancer Society 1992) and the US Preventive Health Services Task Force for high risk individuals (US Preventive Services Task Force in discussion), there is much global variation in the provision and promotion of routine oral cancer examinations. Currently, no national population‐based screening programmes for oral cancer have been implemented in the high‐income countries, although opportunistic screening has been advocated (Brocklehurst 2013). Consequently, individuals will often present for examination at a later stage of the disease, when the risks of significant morbidity and mortality are substantially higher. The British Columbia Oral Cancer Prevention Program (BC OCPP) is addressing this challenge in several ways: by linking community dental practices and referral centres, by creating partnerships between scientists and clinicians that already have resulted in new technologies to enhance early diagnosis, by involving a broad range of stakeholders to ensure population‐based screening and by engaging in provincial, national and international outreach (Rosin 2006). Brocklehurst et al's systematic review identified only one randomised controlled trial using visual examination with a follow‐up period of 15 years which was carried out in India. The authors of the review concluded that opportunistic screening of high risk groups may potentially improve outcomes, although the risk of bias of the included study was high (Brocklehurst 2013).

There is some debate in the literature on anticipated differences in diagnostic accuracy of prospective population‐based invitational screening programmes and a more opportunistic approach (when patients attend their general (dental) practitioner for routine examination or for treatment). In Downer et al's systematic review of test performance in screening for oral cancer and PMD, only prospective investigations of population screening with specified reference standards were included. The pooled sensitivities and specificities were 0.85 (95% CI 0.730 to 0.919) and 0.97 (95% CI 0.930 to 0.982) respectively (Downer 2004). An opportunistic approach that focuses on high risk groups is also possible (McGurk 2010; Sankaranarayanan 1997). A simulation study which used neural network and machine learning techniques suggested opportunistic screening aimed at high risk groups may be both effective and cost‐effective (Speight 2006). However, many individuals with risk factors may not attend the dentist and are therefore not amenable to an opportunistic approach (Netuveli 2006; Yusof 2006).

Reviews assessing the test accuracy of a conventional oral examination as a population screening tool (e.g. Downer 2004; Moles 2002) have highlighted methodological flaws in the primary diagnostic test accuracy studies, although explicit methodological quality assessment of these studies using a validated and widely used checklist was not undertaken.

In this review we have identified screening tests for PMD and cancer of the lip or oral cavity to evaluate the diagnostic accuracy of the COE and the accuracy of the other index tests (Additional Table 1) used as adjuncts to the oral examination in asymptomatic adults. The index tests proposed for evaluation in this review are suitable for use in the community or as part of a dental examination in a general dental practitioners' office. The review includes both prospective investigations of organised screening programmes and prospective opportunistic screening. It is important that this review considered both as individuals screened opportunistically are self selecting and may not be representative of the population of interest. In either scenario, screening may be carried out by dental professionals or healthcare workers. The purpose of the screening is to identify the presence or absence of PMD which require referral to secondary care for definitive diagnosis and possibly treatment. The proposed index tests cannot confirm whether a PMD is cancerous before deciding on referral to secondary care; biopsy with histopathology is currently the only confirmatory method of oral cancer diagnosis.

The Cochrane Oral Health Group has undertaken a number of intervention reviews in the field of treatment of oral and oropharyngeal cancers (Bessell 2011; Furness 2011; Glenny 2010) and screening programmes for the early detection and prevention of oral cancer (Brocklehurst 2013). This screening test accuracy review complements the intervention reviews.