Target condition being diagnosed

The target conditions of interest are oral squamous cell carcinoma (OSCC), the most common form of oral cavity cancer (Scully 2000a), and potentially malignant disorders (PMD), of the lip and oral cavity in patients presenting with clinically evident lesions. A variety of terms have been used internationally to describe clinical presentations that have the potential to become cancer. At a meeting of international oral cancer and precancer experts held in 2005, the concept of precancer, along with issues surrounding classification and definition, aetiology, diagnosis and management was extensively discussed. Through consensus, the term 'potentially malignant disorders' was selected to convey the fact that not all precancerous lesions and conditions will transform to cancer, but there is the potential for malignant transformation (van der Waal 2009; Warnakulasuriya 2007).

The natural history of oral cancer is not fully understood, given variations in disease processes and dysplastic changes in PMD (Napier 2008; Scully 2009). Most oral carcinomas are preceded by PMD, of which erythroplakia, non‐homogeneous leukoplakia, erosive lichen planus, oral submucous fibrosis and actinic keratosis are perhaps the most important (Warnakulasuriya 2007). The concept of a two‐step process of cancer development of the oral mucosa is established (i.e. precursor to established lesion). Oral leukoplakia is the best‐known precursor lesion and between less than 1 and 18% of lesions develop into oral cancer. The original 1978 World Health Organisation (WHO) definition of oral leukoplakia has been revised to read "The term leukoplakia should be used to recognize white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer" (Warnakulasuriya 2007). The presence of epithelial dysplasia can help predict malignant development but the diagnosis is essentially subjective, with not all lesions exhibiting dysplasia, some becoming malignant and some regressing. Carcinoma can also develop from lesions in which epithelial dysplasia was not previously diagnosed. Numerous attempts have been made to relate biological characteristics to the malignant potential of leukoplakias, but finding a definitive characteristic remains elusive (Reibul 2003). 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 calculated a global MTR of oral leukoplakia of 1.36% per year (95% confidence interval 0.69 to 2.03%) based on the prevalence of leukoplakia (Petti 2003), 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 5 years. For example, the incidence of OSCC arising from leukoplakia in Californians was greatest in the second year of follow‐up (11 out of 45; 24%) (Silverman 2004). The proportion of PMD that will develop OSCC is uncertain but low; best estimates suggest a rate of less than 2% per year (Napier 2008).

The early detection and excision of some PMD can prevent malignancy, or if malignancy is detected, there is some evidence that appropriate treatment can reduce disease severity and improve survival rates (Brocklehurst 2010; van der Waal 2009; Warnakulasuriya 2007). Leukoplakias can be treated by a number of methods. According to Lodi et al's systematic review (Lodi 2008), the effectiveness of surgical interventions, including laser therapy and cryotherapy, has not been studied by means of a randomised controlled trial (RCT) with a no treatment/placebo arm. Vitamin A and retinoids have been tested by five RCTs, two studies investigated beta carotene or carotenoids, the other drugs tested were bleomycin (one study), mixed tea (one study) and ketorolac (one study). 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. Where resolution of a lesion is observed, relapses and adverse effects are common.

Technologies to treat and manage oral cancer have progressed substantially, as shown by Cochrane systematic reviews of RCTs (Bessell 2011; Furness 2011; Glenny 2010). Patients presenting with oral lesions persisting for more than 2 to 3 weeks are generally referred to an oral medicine specialist for further investigation and to rule out malignancy (Scully 2000a; Scully 2000b; Scully 2000c). Once progressed to frank malignancy, the traditional treatment is 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 radiotherapy and chemotherapy, adversely affecting an individual's quality of life. The 5‐year survival rate following diagnosis has remained at around 50% for the past 30 years in most countries (Parkin 2001; Warnakulasuriya 2009). 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)

There is no standard practice for patients presenting with clinically evident lesions that may carry a risk of cancer. Factors contributing to this variation include geographical location and access to clinical personnel. A conventional oral examination (COE), a standard visual and tactile examination of the oral mucosa under normal (incandescent) light by a frontline clinician such as a general dentist is a common starting point. This can be considered as an opportunistic 'screen'. The assumption is that an examination is performed to provide an opportunity for 'case‐finding' where necessary. Upon discovering a lesion the clinician will make a subjective judgement based upon the clinical presentation, their clinical experience and training and the resources available to them to decide on the next step. A fungating ulcerative mass that is obviously an advanced malignancy needs little clinical acumen and initiates an immediate referral. As we move earlier in the disease spectrum, the clinical features become progressively less obvious and the judgement as to whether a lesion is, or has, the potential to become dysplastic or even malignant, and hence the next step on the pathway becomes more difficult.

A number of index tests have been proposed for use by frontline clinicians, specialists and 'super‐specialists' (i.e. those who see surveillance populations) as adjuncts to a conventional oral cancer examination for the purpose of improving diagnostic test accuracy (Fedele 2009; Leston 2010; Lingen 2008; Patton 2008; Rethman 2010). These include:

• vital staining (toluidine blue, tolonium chloride);

• oral cytology (e.g. OralCDx brush biopsy);

• light‐based detection (e.g. ViziLite and ViziLite Plus, Microlux/DL, VELscope, Orascoptic DK, Identafi 3000) and oral spectroscopy; and

• blood and saliva analysis.

Vital staining and oral cytology are long available diagnostic adjuncts to a conventional oral examination (Leston 2010; Lingen 2008). In this review, we will restrict vital staining index tests to those applied to a lesion that has been visualized. A companion Cochrane review 'Clinical assessment to screen for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults' will include vital staining index tests in a rinse form, used as a screening adjunct in a general population (Walsh 2012). Other tests such as light‐based detection systems have become commercially available only more recently. Blood analysis and saliva analysis are more novel tests at an early stage of evaluation.

It is worth noting there are regional differences in regulations on the use of some of the above tests. For example, toluidine blue, having been consistently rejected as a stand‐alone technique, is not cleared for use as a stand‐alone screening technique in the United States; it is included in the ViziLite Plus system. However, the toluidine blue‐only component is approved by the FDA as a marking device.

There are a number of different uses for such diagnostic adjuncts dependent on the pathway taken by the patient. Of the index tests listed above, all have the potential to be used as diagnostic or case‐finding adjuncts to the COE by frontline clinicians (Additional Table 1), specialists and 'super‐specialists', to aid in the more accurate diagnosis of oral cancer and PMD. By including these tests, the diagnostic process would be identification of clinically evident lesions on the basis of clinical appearance and criteria and/or findings from the index test(s), followed by biopsy where appropriate. The tests could have a triage role in assisting the general dentist or oral specialist to more accurately identify or assess persistent oral lesions of uncertain significance. 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. A non‐invasive index test or combination of tests adjunctive to the COE that provided 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.

The index tests also have the potential to improve patient diagnosis at a secondary care level. Following referral to a specialist clinic, the most important clinical step is to biopsy the area or areas representing the worst disease. This is simple with a single homogeneous lesion but becomes more complicated when the lesion or lesions become larger and more heterogeneous. Sample site selection may be facilitated by the diagnostic adjuncts, so performance in a secondary care setting becomes important.

Finally, the tests could be useful in a surveillance setting such as a cancer clinic where patients with a history of oral cancer or PMDs are followed at specified times. This population is likely to have had multiple biopsies, surgical procedures to treat cancer or dysplastic changes, or other treatments such as radiation therapy. Monitoring these patients for new disease (they often have field changes) is challenging. The diagnostic adjuncts could be of value in this setting.

Alternative test(s)

Medical imaging techniques such as computer tomography (CT), other forms of tomography and magnetic resonance imaging (MRI) have been used in addition to clinical evaluation. The diagnostic test accuracy of such techniques will not be considered in this review.

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 developing countries as in developed countries, and a threefold increase in mortality. Tobacco use, alcohol consumption, betel quid chewing and low socioeconomic status are the most important risk factors of oral cancer (Conway 2008; Faggiano 1997; La Vecchia 1997; Macfarlane 1995). Men have a higher incidence of oral cancer than women, 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 5 males to 1 female diagnosed with oral cancers in the 1960s to less than 2 to 1 in 2008 (Ferlay 2010). Although traditionally the risk of oral cancer increases with age, the incidence among younger adults has increased in the European Union and the United States (Warnakulasuriya 2009). Technologies to treat and manage oral cancer have progressed substantially, as shown by Cochrane systematic reviews of RCTs (Furness 2011; Glenny 2010). Nevertheless, the 5‐year survival following diagnosis has remained at around 50% for the past 30 years in most countries (Parkin 2001; Warnakulasuriya 2009).

The five year survival rate depends on the site of the cancer, ranging from more than 90% for the lip to 40% for the oropharynx (Cancer Research UK). Oral cancer is often diagnosed at a late stage, when the prognosis is poor and the risks of significant morbidity and mortality are substantially higher (Rusthoven 2010). Oral cancer mortality can be reduced using three approaches: (i) primary prevention, (ii) secondary prevention, screening and early detection, and (iii) improved treatment (Scully 2000a).

Currently, no national population‐based screening programmes for oral cancer have been implemented in developed countries, although opportunistic screening has been advocated (Brocklehurst 2010). 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. A province‐wide programme is being evaluated in British Columbia, Canada but the evaluation is ongoing and no final results have been reported to date (Rosin 2006). Brocklehurst et al's Cochrane systematic review identified one RCT in India. They concluded that the evidence is insufficient to recommend population‐based screening and suggested that opportunistic screening of high risk groups may potentially improve outcomes (Brocklehurst 2010). Accurate case detection and early treatment of oral cancers can substantially improve an individual's morbidity, mortality and quality of life (Scully 2000a; Stell 1982).

There is some uncertainty on the diagnostic accuracy of the index tests listed above. Review studies have identified a number of these tests for oral cancer in individuals with an identified lesion (Leston 2010; Lingen 2008; Patton 2008). The focus of these reviews, however, has been on a description of the sensitivities and specificities of diagnostic tests rather than a comprehensive quality assessment of studies and meta‐analysis of all available data. The index tests have the potential to improve the accuracy of oral cancer diagnosis and to detect the disease at an earlier stage. This could result in improved diagnostic decisions, leading to appropriate treatment pathways and ultimately improved patient outcomes.

In this review we aim to identify diagnostic tests for oral cancer and PMD and to evaluate the diagnostic accuracy of these tests (Additional Table 1) when used as adjuncts to a COE by frontline clinicians, specialists and 'super‐specialists'. 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, and in screening programmes for the early detection and prevention of oral cancer (Bessell 2011; Brocklehurst 2010; Furness 2011; Glenny 2010). This diagnostic test accuracy review will complement the intervention reviews.