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Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions

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Table 1. Index tests for oral cancer and PMDs

Test

Characteristics

Classification of response

Other information

Conventional oral examination (COE)

A standard visual and tactile examination of the oral mucosa under normal (incandescent) light.

The presence of an oral mucosal abnormality with a suspicion of malignancy or potential malignancy is classified as a positive test result; the presence of oral mucosal abnormality without a suspicion of malignancy or potential malignancy is classified as a negative test result.

Traditionally used as a oral cancer screen rather than diagnosis, but its utility is debated (Lingen 2008).

Advantages: quick and easy once trained, minimally invasive.

Disadvantages: oral mucosal abnormalities are not necessarily clinically or biologically malignant; only as small percentage of leukoplakias are progressive or become malignant, COE cannot distinguish between those that are or are not; some precancerous lesions may exist within oral mucosa that appears clinically normal by COE alone (Lingen 2008).

Vital staining (e.g. toluidine blue, tolonium chloride)

Vital staining refers to the use of dyes such as toluidine blue or tolonium chloride to stain oral mucosa tissues for PMD or malignancy (Leston 2010; Lingen 2008; Patton 2008). The procedure is as follows.

  • Pre‐rinse with acetic acid

  • Rinse with water

  • Apply toluidine blue

  • Post rinse with acetic acid

  • Rinse with water

  • Observe mucosa to check for staining.

The result of the test is classified as positive if tissue is stained and negative if no tissue is stained, or equivocal if no definitive result can be obtained.

Advantages: ability to define areas that could be malignant or abnormal but cannot be seen; assess the extent of the PMD for excision.

Disadvantages: benign inflammatory lesions are subject to stain; possibility of failure of some cancerous lesions to stain; possibility of failure of some dysplastic lesions (particularly those with a lower grade or with a thick keratotic surface) to stain; variation in test performance depending on how thorough the test procedures are followed; contraindicated in those who are known to be allergic to iodine.

Brush cytology (e.g. OralCDx brush biopsy)

Brush cytology refers to the microscopic assessment and interpretation of cell samples from PMD that are flaked off from the oral mucosa by the brushing, smearing, scraping or lavage to collect cell samples, which are then sealed on glass slides. They are then analysed using an imaging system that assesses the sampled cells (Leston 2010; Lingen 2008; Patton 2008).

Following analysis, cytopathologists classify test results as positive, atypical or negative.

Advantages: include the ability to collect information from, and detect large or multiple lesions and to access "the basement membrane collecting cells from all three epithelial layers of the oral mucosa. The liquid‐based cytology reduces the problems relating to sampling and fixation and presents a better cytological morphology" (Divani 2009).

Disadvantages: smaller or less obvious lesions may be overlooked; difficulties in detecting lesions when there is necrosis or coagulated blood; inadequate training of operators (Divani 2009); cells are potentially seen out of context.

Light‐based detection (chemiluminescence e.g. ViziLite, ViziLite plus, Microlux DL; tissue fluorescence imaging e.g. VELscope, Identafi 3000; tissue fluorescence spectroscopy)

Light‐based systems to identify malignant and potentially malignant lesions and to highlight their presence through tissue reflectance (Leston 2010; Lingen 2008; Patton 2008) e.g. using Microlux DL, the procedure is as follows (Lingen 2008).

  • Pre‐rinse with acetic acid

  • Use blue‐light light source to visually assess the oral cavity.

ViziLlite Plus also provides a tolonium chloride solution (toluidine blue) to aid in the marking of the lesion for biopsy once the light source is removed.

The result of the test is classed as negative if the appearance of the epithelium is lightly bluish white and positive if the appearance of the epithelium is distinctly white (acetowhite).

Advantages: simple to use; non‐invasive; do not require consumable reagents; provide real time results; can be performed by a wide range of operators after a short training period.

Disadvantages: the necessity of a dark environment; high initial set up (for VELscope) or recurrent costs (for ViziLite in low income countries); lack of permanent record unless photographed; inability to objectively measure visualisation results.

Blood and saliva analysis

These novel technologies are at an early stage of development and evaluation. Analysis of blood or saliva samples which tests for the presence of biomarkers of PMD and oral cancer (Brinkmann 2011; Lee 2009; Li 2006).

Cutoff probabilities vary widely and are dependent on the individual biomarker or combination of biomarkers examined.

Advantages: non‐invasive (saliva tests) or minimally invasive (blood tests).

Disadvantages: there is a tendency for the estimated diagnostic accuracy of new health technologies to decline over time as evidence from independent evaluations accumulate (Wyatt 1995). This bias, which can be substantial, has been demonstrated in other domains, e.g. acute abdominal pain (Liu 2006) and clinical decision support systems (Garg 2005). Promising biomarker tests in several clinical areas were eventually been shown to be disappointing (Buchen 2011). It remains to be seen whether this is the case with oral cancer and PMDs.

PMD = potentially malignant disorders

Figures and Tables -
Table 1. Index tests for oral cancer and PMDs
Table 2. Indicators for the assessment of quality (QUADAS‐2)

Domain

Patient selection

Index test

Reference standard

Flow and timing 

Description

Describe methods of patient selection.

Describe included patients (characteristics, prior testing, presentation and severity of the target condition (class), intended use of index test and setting). 

Describe the index test(s) and how it was conducted and interpreted. Describe the sequence of tests, any training or calibration of clinicians (levels of agreement should be reported; where this is measured by the kappa statistic, acceptable values range from 0.61 (moderate agreement) to 1.00 (almost perfect agreement) (Landis 1977)), any procedures taken to ensure blinding of examiners, post‐hoc or a priori threshold specification, any conflict of interest or commercial funding. Methods of site selection should be clearly documented.

Describe the reference standard and how it was conducted and interpreted. Ideally, the biopsied tissue should be examined by more than one pathologist. If there is a lack of agreement any methods for reaching consensus should be clearly documented. Any measures taken to ensure pathologists were blinded to the results of the index tests should be documented, along with the sequence of reference and index tests. Methods of site selection should be clearly documented.

Describe the characteristics and proportion of patients who did not receive the index test(s) and/or reference standard, who received a reference standard other than the scalpel biopsy, or who were excluded from the 2 x 2 table (refer to flow diagram). Describe the time interval and any interventions between index test(s) and reference standard. The length of time between the index test and reference standard should be short in the majority of cases. If the period elapsed between index test and reference standard is greater than 2 weeks then this will be considered an unacceptable delay.

Signalling questions

(Yes/No/Unclear)

Was a consecutive or random sample of patients enrolled?

Classify as 'Yes' if consecutive patients or a random sample of individuals were recruited.

Classify as 'No' if non‐consecutive patients or a non‐random sample of individuals were recruited.

Classify as 'Unclear' if patient selection was not clearly described.

Was calibration of examiners undertaken and results reported?

Classify as 'Yes' if the examiners participated in dedicated training and calibration was reported to an acceptable standard.

Classify as 'No' if the examiners did not participate in dedicated training or was not assessed, or training was undertaken but calibration was not to an acceptable standard.

Classify as 'Unclear' if the information on training and calibration was not stated.

Is the reference standard likely to correctly classify the target condition?

Classify as 'Yes' if the biopsy was independently confirmed by at least two qualified pathologists.

Classify as 'No' if the biopsy was not independently confirmed by at least two qualified pathologists, or there was lack of agreement between pathologists.

Classify as 'Unclear' if the study does not state who confirmed the biopsy. 

Was there an appropriate time interval between the index test(s) and reference standard?

Classify as 'Yes' if the delay between the index test(s) and reference standard is considered acceptable for the majority of participants.

Classify as 'No' if the delay between the index test(s) and reference standard is considered unacceptable for the majority of participants.

Classify as 'Unclear' if the delay between the index test(s) and reference standard is not explicitly stated.

Did the study avoid inappropriate exclusions?

Classify as 'Yes' if patients with either class I or class II lesions were recruited.

Classify as 'No' if only patients with class I lesions were recruited.

Classify as 'Unclear' if class of lesions was not clearly described.

Were the index test results interpreted without knowledge of the results of the reference standard?

Classify as 'Yes' if interpreters of index test results clearly do not know results of biopsy/histopathology.

Classify as 'No' if interpreters of index test results clearly know results of biopsy/histopathology.

Classify as 'Unclear' if study did not provide any information on whether interpreters of index tests were blinded to biopsy/histopathology.

Were the reference standard results interpreted without knowledge of the results of the index test?

Classify as 'Yes' if pathologists clearly do not know the index test results when interpreting biopsied tissues.

Classify as 'No' if pathologists know the results of index test results when interpreting biopsied tissues.

Classify as 'Unclear' if the study did not provide any information on whether the pathologists were blinded to the index test results.

Did all patients receive the same reference standard?

Classify as 'Yes' if the same reference standard was used in all participants.

Classify as 'No' if the same reference standard was not used in all participants.

Classify as 'Unclear' if it is unclear whether different reference standards were used.

Where multiple index tests were used, were the results of the second index test interpreted without knowledge of the results of the first index test?

Classify as 'Yes' if index test results were interpreted without knowledge.

Classify as 'No' if the index test results were interpreted with knowledge.

Classify as 'Unclear' if it is unclear whether the results of the second index test were interpreted without knowledge of the results of the first index test?

Were all patients included in the analysis?

Classify as 'Yes' if all patients were included in the analysis.

Classify as 'No' is only some patients were included in the analysis.

Classify as 'Unclear' if it is unclear whether all patients were included in the analysis. 

If a threshold was used, was it prespecified?

Classify as 'Yes' if the threshold was prespecified.

Classify as 'No' if the threshold was not prespecified.

Classify as 'Unclear' if it is unclear whether the threshold was prespecified.

Were any conflicts of interest stated?

Classify as 'Yes' if the study declared no conflict of interest.

Classify as 'No' if the study if the study declared a conflict of interest.

Classify as 'Unclear' there was no information on conflict of interest.

Risk of bias: High/Low/Unclear

Could the selection of patients have introduced bias?

Could the conduct or interpretation of the index test have introduced bias?      

Could the reference standard, its conduct, or its interpretation have introduced bias?

Could the patient flow have introduced bias? 

Concerns regarding applicability: High/Low/Unclear

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

Figures and Tables -
Table 2. Indicators for the assessment of quality (QUADAS‐2)