Early Detection of Malignancies and Potential Malignancies in the Oral Cavity - a systematic review

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Early Detection of

Malignancies and Potential

Malignancies in the Oral

Cavity - a systematic review

Lars Salomonsson Philip Wadelius

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ABSTRACT

Oral cancer is a major health problem, with over 500000 patients diagnosed each year. Although progress has been made in regards to both diagnosis and treatment, the overall 5-year survival rate has not changed much in the last 30 years and still relatively static at around 50 %. This high mortality rate is related to late diagnosis of oral malignancies. At stages III and IV the 5-year survival rate is as low as 30 %, however if diagnosed at stage I the survival rate increases substantially to approximately 80 %. Research in to viable methods for early detection of oral malignancies and potential malignancies has the potential to save lives and reduce suffering for many people word wide. The purpose of this systematic review is to find an effective and practical diagnostic test for early detection of malignancies and potential malignancies in the oral cavity. Electronic database searches were conducted in English on the 4th of February 2017,

using PubMed medical database, publication date 2005 or later. Inclusion criteria: Diagnostic

Test Accuracy studies for oral malignancies and potential malignancies in human patients with gold standard reference test. Search yielded 166 records, titles and abstracts was screened and evaluated, 19 records was included. Included studies were assessed in detail regarding

methodological quality and diagnostic accuracy. 19 studies with a total of 11575 participants

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INTRODUCTION

Oral cancer is a great health problem worldwide with over 500000 patients getting diagnosed each year (Kujan et al., 016). The prevalence is largely connected to socioeconomic status and is therefore much higher in third world countries e.g. India (Kujan et al., 2016). Major risk factors are smoking and alcohol consumption, which are also considered to have a synergistic effect. Although progress has been made in both diagnosis and treatment of oral cancer, the overall 5-year survival rate has not changed considerably in the last 30 years and is still around 50 % (Carreras-Torras et al,. 2015). This is due to the fact that most cases of oral cancer isn’t diagnosed until it has reached a late stage III-IV (Carreras-Torras et al., 2015). At this stage the 5-year survival rate is as low as 30 %, but if diagnosed at stage I the survival rate is 80 % (Carreras-Torras et al,. 2015) Making oral cancer research a field where considerable development is needed, especially regarding early diagnosis. Oral cancer is defined as malignant neoplasm on the lip or in the mouth and 90 % of oral cancer consists of oral squamous cell carcinoma (OSCC) (Carreras-Torras et al., 2015).

Oral potentially malignant disorders

Oral potentially malignant disorders (OPMD’s) are chronic lesions or conditions characterized by a potential for malignant transformation (Khan et al., 2016). OPMDs can be divided into two groups; precancerous lesions and precancerous conditions (Warnakulasuriya et al., 2007). Leukoplakia, erythroplakia and palatal lesions caused by reverse smoking are classified as precancerous lesions. Submucous fibrosis, actinic keratosis, lichen planus and discoid lupus erythematosus are classified as precancerous conditions.

Leukoplakia

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nodular and/or verrucous surface, be mixed in color and show both white and red areas. Those lesions with both white and red plaque are to be called ´erythroleukoplakia´. Non-homogenous lesions have a much greater risk of malignant transformation than the homogenous (Warnakulasuriya et al., 2007).

To exclude any other disorders a biopsy followed by histopathological analysis must be carried out. The lesion is then characterized as leukoplakia with or without dysplasia. If the lesion is dysplastic, an excision is performed and if it is considered to be non-dysplastic it is diagnosed as frictional keratosis (Villa et al,. 2016).

Erythroplakia

Oral erythroplakia is a red, flat, smooth or granulated patch found on the oral mucosa. As the case with leukoplakia, all other causes/conditions (e.g. Erythematous lichen planus, infections et cetera) must be ruled out before erythroplakia can be diagnosed. The 1978 definition of erythroplakia is (Warnakulasuriya et al., 2007): ‘A fiery red patch that cannot be characterized clinically or pathologically as any other definable disease’. Erytroplakia is quite rare and are most often seen in combination with white patches i.e. erythroleukoplakia. Erythroplakia is the OPMD considered to have the highest risk of malignant transformation (Warnakulasuriya et

al., 2007).

Oral lichen planus

Oral lichen planus (OLP) is a chronic inflammatory disorder caused by an increased number of T lymphocytes in the oral mucosa, which leads to a thickening and hyperkeratosis of the epithelium. The aetiology to what triggers the gathering of T lymphocytes is not known. Clinical features of OLP are a hyperkeratinisation of the mucosa, often in a reticular fashion with white striations. The lesion can also show red and erosive patterns which may give burning symptoms. White plaque that resembles leukoplakia is also a quite common trait of OLP (Warnakulasuriya et al., 2007).

Objective

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MATERIALS AND METHOD

Ethical considerations

Potential ethical problems are bias, or otherwise low quality, in the included articles. As a result of this, low quality methods of diagnosis could be used which in turn could lead to false negatives and/or false positives. Because of this, specific exclusion and inclusion criteria were used in the process of identifying relevant studies to include in this review. The Ethics Forum at the Department of Odontology found that appropriate ethics considerations have been integrated into this degree project.

Inclusion criteria

For this review we have used an inclusion/exclusion system abbreviated as PICOS (Population,

Index test, Control, outcome, Study design). Inclusion criteria are specified below.

Population

Patients, human, no groups excluded.

Index test

Clinical tests used alone or in combination.

Control

Biopsy followed by histological analysis.

Outcome

1. All types of PMDs (Potentially Malignant Disorders) located in the oral cavity, including leukoplakia, erytroplakia, lichen planus and lupus erythematosus.

2. All types of Malignancies located within the oral cavity.

Study design

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Methodology for identifying approppriate studies

Database searches were conducted on the 4th of February 2017, using PubMed medical database. Search terms and specification is presented in figure I.

Selection and selection quality control

Abstracts and titles from identified studies were screened by two authors as seen in flowchart in figure 2 as “stage I” All titles and abstracts were read by both authors. In the case of ambiguity as to include or exclude, full articles was read, followed by discussion. Excluded articles from “stage I” is presented in table 1. In “stage II” full text articles were read by both authors, excluded articles is presented in table 2. Finale analysis was derived from remainder of studies, seen in flowchart as “Included in review” and is specified in table 3.

Scientific quality control of included studies

In order to evaluate the strengths and weaknesses of this review we conducted an assessment of the included studies in regard to scientific quality and risk of bias. We used a system called QUADAS; a tool for the quality assessment of diagnostic accuracy studies.

RESULTS

Results of electronic searches

A total of 166 records were identified via electronic searches in the PubMed database. 166 records were screened by title and abstract, 131 records were excluded from the review as they did not conform to the inclusion criteria. 35 records were examined in full text as prospective inclusion candidates, by both reviewers, 16 records was excluded at this stage. A total of 19 records aligned with all inclusion criteria. These 19 records were included in the review. The most frequent reason for exclusion was failure to accommodate the Diagnostic Test Accuracy study design criteria.

Scientific and methodological quality of included studies

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assessment, results are presented in 6 categories based on the general form of diagnostic test. Summary of results regarding scientific and methodological quality is presented in figure 3.

Brush biopsy sampling

In the category of Brush Biopsy Sampling (BBS) 10 studies with a total of 599 participants was identified. Apart from the specific location of each study, settings were practically uniform. Setting consisted of clinical and clinical laboratory environments in, or in close proximity to the odontological educational institutions of each location. Locations as follows; Bologna, Italy (Morandi et al., 2015), London, United Kingdom (Graham et al., 2015), Cordoba, Argentina (Gonzalez Segura et al., 2015), Mainz, Germany (Kammerer et al., 2013), Amsterdam, the Netherlands (Graveland et al., 2013), Santiago de Compostela, Spain (Seijas-Naya et al., 2012), Leipzig, Germany (Remmerbach et al., 2011), Allahabad, India (Mehrotra et al., 2011), Mainz, Germany (Koch et al., 2011), Mashhad, Iran (Delavarian et al., 2010),

Participant selection

Although small variations regarding patient selection between studies were seen, all studies in this category was deemed to have a relevant patient group in respect to their objective (Morandi

et al., 2015; Graham et al., 2015; Gonzalez Segura et al., 2015; Graveland et al., 2013; Mehrotra et al., 2011; Koch et al., 2011; Delavarian et al., 2010; Seijas-Naya et al., 2012; Kammerer et al., 2013; Remmerbach et al., 2011). Variations consisted of that in some studies only e.g. “oral

premalignant and malignant lesions” (Delavarian et al., 2010) were includes. Some studies included very small changes in the oral epithelium e.g. “oral lesion deemed to be minimally suspicious by clinical examiner” (Mehrotra et al., 2011), while some hade a wider more general inclusion criteria e.g. “suspicious mucosal lesions” (Koch et al., 2011).

Inclusion criteria were also well defined in all records included in the BBS-category (Morandi

et al., 2015; Graham et al., 2015; Gonzalez Segura et al., 2015; Graveland et al., 2013; Mehrotra et al., 2011; Koch et al., 2011; Delavarian et al., 2010; Seijas-Naya et al., 2012; Kammerer et al., 2013; Remmerbach et al., 2011).

Reference test, time delay and risk of verification bias regarding refenrece test analasys

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(Macey et al., 2015). As stated in the inclusion criteria all records in the present systematic review includes excisional biopsy followed by histological analysis.

In 2 studies it was not reported who or how the excisional biopsy and histological analysis was carried out. In addition, the reference test was carried out before the index test, thus a slight risk of verification bias (Remmerbach et al., 2011; Gonzalez Segura et al., 2015).

In 1 study it was not specified if the index test was performed before or after the reference test, however it was specified that, for all subjects, reference test samples was collected either 3 weeks before or 3 weeks after index test samples (Seijas-Naya et al., 2012).

The other 7 studies were deemed as comprehensive in reporting of all matters concerning reference test and reference test analysis. (Morandi et al., 2015; Graham et al., 2015; Graveland

et al., 2013; Mehrotra et al., 2011; Koch et al., 2011; Delavarian et al., 2010; Kammerer et al.,

2013). We judge the risk of verification bias, in the category Brush Biopsy Sampling, as low.

Index test as part of reference test

The index test was not a part of the reference test for any studies in this category (Morandi et

al., 2015; Graham et al., 2015; Gonzalez Segura et al., 2015; Graveland et al., 2013; Mehrotra et al., 2011; Koch et al., 2011; Delavarian et al., 2010; Seijas-Naya et al., 2012; Kammerer et al., 2013; Remmerbach et al., 2011).

Blinding of test results and clinical information

Clinical information and histological analysis results were blinded to the pathologists in 4 studies (Morandi et al., 2015; Kammerer et al., 2013; Mehrotra et al., 2011; Koch et al., 2011). Not blinded or not reported in 5 studies (Graham et al., 2015; Gonzalez Segura et al., 2015; Graveland et al., 2013; Seijas-Naya et al., 2012; Remmerbach et al., 2011). In 1 study the pathologist had access to clinical information, however blind to histological reference information (Delavarian et al., 2010).

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Reporting of corrupted results and patient drop-off.

In 9 studies all patients, including drop-off, and samples were accounted for. However none of the studies reported any corrupted results (Morandi et al., 2015; Gonzalez Segura et al., 2015; Graham et al., 2015; Graveland et al., 2013; Seijas-Naya et al., 2012; Remmerbach et al., 2011; Mehrotra et al., 2011; Koch et al., 2011; Delavarian et al., 2010).

In 1 study all patients and samples was accounted for. Corrupted results were also reported (Kammerer et al., 2013).

We judge the risk of bias regarding patient drop-off and reporting on corrupted results for the

BBS-category as acceptable.

Tissue autofluorescence

In this category (tissue autofluorescence), 4 studies with a total of 2453 participants was identified (Huff et al., 2009), (Paderni et al., 2011), (Rana et al., 2012), (Hanken et al., 2013). Settings varied from a private dental practice Cleveland, Ohio, USA (Huff et al., 2009), a hospital in Palermo, Italy (Paderni et al., 2011), Hannover Medical School in Hannover, Germany (Rana et al., 2012), University Medical Center Hamburg-Eppendorf in Hamburg, Germany (Hanken et al., 2013).

Patient selection

All studies in this category had a relevant patient group to their respective objective and well-defined inclusion criteria, e.g. in two studies OSCC was excluded (Rana et al., 2012; Hanken

et al., 2013) and in one case all regular recall patients age 12 and above was included, regardless

of other patient specifics (Huff et al., 2009), one study excluded patients without any oral lesion (Paderni et al., 2011). Specific methods of patient recruitment were not extensively reported by these studies (Huff et al., 2009; Paderni et al., 2011; Rana et al., 2012; Hanken et al., 2013).

Reference test

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studies in this category was considered as low risk of classification bias regarding reference test diagnosis.

Time delay

In three studies, time delay was minimal between index and reference test, as the biopsy area was indicated with the index test (Paderni et al., 2011; Rana et al., 2012; Hanken et al., 2013). Risk of progression bias was judged as low. One study however had an intermediary test before the gold standard reference test, time between tests was not reported (Huff et al., 2009) risk of progression bias was deemed unclear.

Risk of verification bias regarding reference test analysis

In three studies, positive index tests was tested by the same reference test (Paderni et al., 2011; Rana et al., 2012; Hanken et al., 2013). In one study, only 2 of a total of 8 index test positives was verified by reference test (Huff et al., 2009). Also the invasive nature of the reference test precludes negative index tests to be confirmed, as it is based on excisional biopsy of a well-defined lesion. We judge all 4 studies in this category to have risk of verification bias.

In this category of index tests, no studies have a reference test which is directly dependent on the respective index tests (Huff et al., 2009; Paderni et al., 2011; Rana et al., 2012; Hanken et

al., 2013)

Blinding of test results

Index test analysis were blind to reference test results in all 4 studies (Huff et al., 2009; Paderni

et al., 2011; Rana et al., 2012; Hanken et al., 2013). Reference test analysis was also blinded

in 2 studies (Hanken et al., 2013; Paderni et al., 2011). In the other 2 studies blinding was not reported for reference test analysis (Rana et al., 2012; Huff et al., 2009).

Clinical information

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Reporting of corrupted results and participant drop of

In all 4 studies included in this category, all participants was reported and accounted for (Huff

et al., 2009; Paderni et al., 2011; Rana et al., 2012; Hanken et al., 2013). Potentially corrupted

or otherwise inconclusive results was not specifically addressed in these studies (Huff et al., 2009; Paderni et al., 2011; Rana et al., 2012; Hanken et al., 2013).

Metachromatic dye staining

In this category, one study with a total of 7975 participants was identified. The study was mass screening RCT carried out in Keelung, Taiwan, in a dental practice setting (Su et al., 2010)

Patient selection was conducted via invitation and specific high-risk criteria (Su et al., 2010). A high-risk population was recruited on basis of OPML risk factors (Su et al., 2010). We judge the patient group as applicable since the study was a mass screening effort (Su et al., 2010).

Reference test

Index test positive patients were referred to the National Taiwan University Hospital and reference test was carried out by one oral pathologist (Su et al., 2010).

Time delay

Time difference between index and reference test was a maximum of 14 days (Su et al., 2010).

All positive index tests also underwent confirmation by the reference test (Su et al., 2010). The nature of the reference test precludes negative index tests to be confirmed, as it is based on excisional biopsy of a well-defined lesion.

No index test was a part of the reference test in this category (Su et al., 2010).

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Clinical information was not extensively reported (Su et al., 2010) therefor we deemed it unclear as to what degree the experimental conditions was in agreement with standard clinical conditions.

In this category, corrupted or otherwise unusable, results were reported and all patients was accounted for (Su et al., 2010).

Saliva sampling

In this category, two studies with a total of 120 participants were identified. (Wang et al., 2014a; Wang et al., 2014b). Studies was conducted in Sichuan, China, 2012- 2013 (Wang et al., 2014a) and 2014 (Wang et al., 2014b).

Participants from both studies were recruited from “West China Hospital of Stomatology, West China School of Stomatology, Sichuan University” (Wang et al., 2014a; Wang et al., 2014b). Participants, from both studies, total of 60 patients with previously histopathological confirmed OSCC in different stages of the disease. Controls in total was 60 healthy individuals (Wang et

al., 2014a; Wang et al., 2014b). We judge patient selection in this category (Saliva sampling) as adequate, however, not optimal as recruitment method was not reported.

Reference test

The gold standard reference test for diagnosis of OED and OSCC is excisional biopsy followed by histological analysis (Macey et al., 2015), as stated in the inclusion criteria. Although it is not described how, or by whom the reference test is given (Wang et al., 2014a; Wang et al., 2014b) we deemed the reference test to be correct as it is stated that the gold standard (Macey

et al., 2015) was used as reference test (Wang et al., 2014a; Wang et al., 2014b).

Time delay

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All positive index tests was tested by the same reference test (Wang et al., 2014a_{; Wang et al.,}

2014b_{), however the invasive nature of the reference test precludes negative index tests to be}

confirmed, as it is based on excisional biopsy of a well-defined lesion.

The index test was not a part of the reference test for any studies in this category (saliva

sampling) (Wang et al., 2014a; Wang et al., 2014b).

All reference tests, in this category, were carried out before index tests and is therefore source of potential bias, as blinding was not reported for any studies in this category (Wang et al., 2014a, Wang et al., 2014b).

As the index tests in this category is of a quantitative nature (Wang et al., 2014a; Wang et al., 2014b) clinical information is not relevant.

Studies included in this category did not report any corrupted results (Wang et al., 2014a_{; Wang}

et al., 2014b_{). All participants were accounted for studies in the present category (Wang et al.,}

2014a; Wang et al., 2014b).

Blood sampling

In this category, one study with a total of 328 participants was identified. The study was carried out in a hospital setting, Mumbai, India (Sahu et al., 2015)

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Reference test

The gold standard reference test for diagnosis of OEDand OSCC is excisional biopsy followed

by histological analysis (Macey et al., 2015), as stated in the inclusion criteria.

It is not described how or by whom the reference test is given, however it is clearly stated that the gold standard reference test was given (Sahu et al., 2015).

Time delay

As the reference test was given before the index test and no time delay was reported, we judged the risk of progression bias as unclear for the one and only study in this category (Sahu et al., 2015).

The entirety of the experiment group was diagnosed beforehand by the reference test and all participants underwent the index test (Sahu et al., 2015). The nature of the reference test precludes negative index tests to be confirmed, as it is based on excisional biopsy of a well-defined lesion.

The index test was not a part of the reference test for the study included in this category (Sahu

et al., 2015).

Reference test was blind to index test as it was performed beforehand, however it is unclear as to what degree the index test was blind to the reference test as it was not reported in the only study included (Sahu et al., 2015) in this category.

As the index test in this category is of a quantitative nature (Sahu et al., 2015) clinical information is not relevant.

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In this category, one study with a total of 101 participants was identified. The study was carried out in Taipei, Taiwan, in a hospital setting (Chu et al., 2012).

Although the method for patient selection was unclear for this study, we deemed the selected patient group to be representative from a study aim perspective (Chu et al., 2012). The study targeted a high-risk group of OSCC follow-up patients (Chu et al., 2012).

Reference test

The gold standard reference test for diagnosis of OPML and OSCC is excisional biopsy followed by histological analysis, as stated in the inclusion criteria. Although it was not specified exactly when or by whom diagnosed the OSCC, the analysis method was well described and judge as acceptable (Chu et al., 2012).

Time delay

Time delay between index test was not reported, hence judged as unclear (Chu et al., 2012).

All patients who had a positive index test also underwent confirmation by the reference test (Chu et al., 2012). The nature of the reference test precludes negative index tests to be confirmed, as it is based on excisional biopsy of a well-defined lesion.

The index test was not a part of the reference test (Chu et al., 2012).

Index test analysis and diagnosis was performed before the reference test was given (Chu et al., 2012). Blinding of index test results is unclear as it was not reported (Chu et al., 2012).

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Reporting of corrupted results and participant drop out

Corrupted, or otherwise unusable, results were reported. All patient was accounted for (Chu et

al., 2012).

Test methods in detail and diagnostic accuracy findings

Brush biopsy sampling

Molecular screening of oral precancer.

Objectives of the study were to evaluate brush biopsy as a non-invasive screening method, and to assess the value of molecular markers to identify patients at risk for oral cancer. Brush biopsies and biopsies were collected from 43 patients with oral leukoplakia. All brush biopsies were analyzed and investigated for loss of heterozygosity at chromosomes 3p, 9p, 11q and 17p using microsatellite markers. The biopsies were also immunohistochemically staind for p53, TP53 mutation analysis and histopathological grading were performed to detect genetic changes. Using brush biopsy, the sensitivity to detect genetic changes in the lesions was 45 %, and the specificity was 100 % (Graveland et al., 2013).

Exfoliative cytology as a tool for monitoring pre-malignant and malignant lesions based on combined stains and morphometry techniques.

The aim of this study was to determine the efficacy of PAP staining in combination with

AgNOR staining, and morphometric analysis utilizing brush biopsy, with the Medibrush®Plus

brush. The purpose was to detect malignant changes, both as a means for initial population monitoring and as a follow up examination for patients diagnosed with oral cancer. 34 patients with confirmed OC (n=20) or OPMD (n=14) was enrolled in the study. Two brush biopsies were performed on the lesions of all patients. Two samples, of clinically healthy oral epithelia, was also taken as a healthy control, from the opposite side of the lesion. The sensitivity and the specificity was 90 % respectively (Gonzalez Segura et al., 2015).

DNA methylation analysis by bisulfite next-generation sequencing for early detection of oral squamous cell carcinoma and high-grade squamous intraepithelial lesion from oral brushing.

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intraepithelial lesions (HG-SIL), 9 with low-grade squamous intraepithelial (LG-SIL), 9 with oral lichen planus (OLP), and 8 healthy donors were included. Statistical significance between lesions and a pool of healthy donors were evaluated with the Mann–Whitney U test. ZAP70 was found to be hypermethylated in 100 % of OSCC and HG-SIL and in 28.6 % of LG-SIL. GP1BB hypomethylation was detected in 90.9 % OSCC and HG-SIL and in 37.5 % of LG-SIL. MiR137 was hypermethylated in 100 % of OLP, 44.4 % of OSCC, 40 % HG-SIL, and 25 % LG-SIL. KIF1A hypermethylation was found to be associated with TP53 mutations (p < 0.0001) (Morandi et al., 2015).

A dielectrophoretic method of discrimination between normal oral epithelium, and oral and oropharyngeal cancer in a clinical setting.

The purpose of this study was to assess the preliminary diagnostic validity of a new technology platform based on dielectrophoresis, by examining if oral and oropharyngeal carcinoma cells, and cells from healthy oral mucosa, exhibit differences in electro-physiological profile. 57 patients participated in the study. Oral and oropharyngeal carcinoma (OOPC) oral brush biopsy samples were collected from 45 patients, (using the Rovers® Orcellex® Brush). 21 healthy control samples of oral mucosa were collected from 12, clinically healthy individuals, using the same method. The OOPC-cells and the cells from the healthy controls were then analyzed with a prototype platform, based on dielectrophoresis, using median membrane midpoint frequency as the main analysis parameter. The sensitivity and specificity were 81.6 % and 81.0 %, respectively (Graham et al., 2015).

The efficacy of oral brush biopsy with computer-assisted analysis in identifying precancerous and cancerous lesions.

The aim of this study was to evaluate the diagnostic accuracy of brush biopsy, with computer-assisted analysis, in identifying oral premalignant and malignant lesions. The study included 85 patients, each presenting a, clinically minimally suspicious, white or red lesion with unknown etiology (no obvious etiology such as trauma or infection). Brush biopsies and scalpel biopsies were performed on all patients. The oral brush biopsy samples were collected using a specially

designed brush. The samples were then sent to OralCDx Laboratories® for computer-assisted

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changes of uncertain diagnosis), positive for dysplasia or carcinoma, negative (normal cells) and inappropriate (incomplete trans epithelial sample). The results of the brush biopsies were compared to the ”gold standard” scalpel biopsies. Sensitivity of brush biopsy: 96.3 %; 95 % CI, 87 %-100 %. Specificity of "positive" brush biopsy result: 100 %; 95 % CI, 93 %-100 %. Specificity of "negative" result: 100 %; 95 % CI, 93 %-100 %. Specificity for "atypical" brush biopsy result: 90.4 %; 95 % CI, 82 %-97 % (Mehrotra et al., 2011).

Diagnostic efficiency of differentiating small cancerous and precancerous lesions using mucosal brush smears of the oral cavity--a prospective and blinded study.

The aim of this study was to assess the diagnostic accuracy of oral brush biopsy to identify early malignancy in oral lesions. The study consisted of 135 patients, presenting either an oral mucosal lesion, previously clinically diagnosed as squamous cell carcinoma (SCC), or a suspicious epithelial lesion. 186 brush biopsies of suspicious mucosal lesions were obtained, using the Cytobrush®Plus GT. Immediately after the brush biopsy, a conventional scalpel biopsy was performed on the exact same site as the brush biopsy, by the same examiner. The brush biopsy samples were stained with hematoxylin and compared with the histology of the conventional excision biopsies. The sensitivity for identifying SCC was 88.5 %. High-risk lesions including squamous intraepithelial neoplasia (SIN II, SIN III) and SCC were identified with a sensitivity of 86.4 %. Depending on the cytopathologic definition for malignancy and the tumor size, the test accuracy varied: by stretching the cytopathologic criteria for malignancy by defining all dysplastic or malignant cytopathologic findings as positive, the sensitivity was increased to 95.2 % at the expense of the specificity, which was reduced from 94.9 % to 82.3 %. Separately analyzing SCCs of less than 20 mm, the sensitivity was reduced by 9.5 % to 78 % (Kock et al., 2011).

Evaluation of the diagnostic value of a Modified Liquid-Based Cytology using OralCDx Brush in early detection of oral potentially malignant lesions and oral cancer.

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study, the OralCDx® brush biopsies were visually examined at a cytopathology laboratory without being analyzed using computer-assisted analysis. This, according to the authors, was because there was a lack of laboratories that perform computer-assisted analysis on the OralCDx®. Sensitivity and specificity were 88,8 % and 100 % respectively (Delavarian et al., 2010).

Applications of OralCDx® methodology in the diagnosis of oral leukoplakia.

This study aims to assess the efficacy of the brush biopsy technique, OralCDx ®, as a method for early diagnosis and monitoring potentially malignant disorders. This controlled clinical trial had 24 participants. These patients all showed both clinical and histological lesions consistent with oral leukoplakia. One sample was taken from each patient using the OralCDx ® brush. The brush biopsies were analyzed using computer assisted sample analysis. To evaluate the diagnostic accuracy, a scalpel biopsy sample was also taken from each patient. This was performed either three weeks prior or after the brush biopsy. When comparing test results using from the brush biopsies and conventional biopsies, the sensitivity was 72,7 % and the specificity were 92.3 %. (95 % CI 50.6-99.4 %) (Seijas-Naya et al., 2012).

Prospective, blinded comparison of cytology and DNA-image cytometry of brush biopsies for early detection of oral malignancy.

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Oral brush biopsy analysis by matrix assisted laser desorption/ionisation-time of flight mass spectrometry profiling--a pilot study.

The objective of this study was to develop pre-symptomatic screening detection of OSCC by a brush biopsy. 37 participants were included in the study. At least four brush biopsies were collected from each of the 27 patients, who had previously been diagnosed with OSCC (via scalpel based histology). 40 brush samples were taken from 10 healthy patients, these were used as controls. The samples were analyzed using a MALDI-TOF mass spectrometry. The Sensitivity and the specificity were 100 % and 93 % respectively (Remmerbach et al., 2011).

Tissue autofluorescence

The detection of oral premalignant lesions with an autofluorescence based imaging system (VELscopeTM)–a single blinded clinical evaluation

The aim of this study was to examine the usefulness of the Velscope as a diagnostic tool in early detection of OPMD’s. 120 patients with suspicious oral premalignant lesions were enrolled in the study. The patients were randomly divided into two groups, both groups were examined with conventional white light examination (COE) and then the experimental group was examined using the Velscope. When the COE and the Velscope was used in combination the sensitivity was 97,9 % and the specificity was 41,7 % (Hanken et al., 2013).

Sensitivity of direct tissue fluorescence visualization in screening for oral premalignant lesions in general practice

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Direct visualization of oral-cavity tissue fluorescence as novel aid for early oral cancer diagnosis and potentially malignant disorders monitoring.

The purpose of this study was to evaluate the autofluorescence visualization device (Velscope) as an accessory examination tool in addition to the visual examination with incandescent white light in clinically screening for OPMD’s and malignant oral disorders. 175 patients, all with a minimum of one clinical oral lesion was included in the study. All patients first underwent visual examination using white light, then examination with Velscope and at last all lesions were biopsied. The sensitivity and specificity of the Velscope in combination with the white light examination was 65.5 and 97.4 respectively (Paderni et al., 2011).

Clinical evaluation of an autofluorescence diagnostic device for oral cancer detection: a prospective randomized diagnostic study

The purpose of this study was to evaluate the autofluorescence visualization device (Velscope) as an accessory examination tool in addition to the visual examination with incandescent white light. 289 patients were enrolled in the study. Both the experimental group and the control group were first visually examined with incandescent white light. The experimental group was then visually examined in a dark room with the Velscope. The sensitivity and specificity of the Velscope in combination with the white light examination was 100 % and 74 % respectively (Rana et al., 2012).

Metachromatic dye staining

A Community-based RCT for Oral Cancer Screening with Toluidine blue

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Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma

The aim of this study was to examine potential biomarkers in saliva for early diagnosis of OSCC. Saliva samples were collected from 30, previously untreated patients with OSCC (Stage I-IV). The samples were analyzed using an ultra-performance liquid chromatography (UPLC) mass spectrometry. Four biomarkers were evaluated and analyzed; choline, betaine, pipecolonic acid and L-carnitine. Choline, betaine, pipecolonic acid were up regulated in patients with OSCC and L-carnitine was down regulated, in comparison to the healthy control group. The sensitivity was 100 % and the specificity was 96.7 % (Wang et al., 2014a).

The early diagnosis and monitoring of squamous cell carcinoma via saliva metabolomics

The aim of this study was to examine potential biomarkers in saliva for early diagnosis of OSCC. Saliva samples were collected from the 30 patients. All of whom were diagnosed with OSCC (Stage I-IV). None of the participants hade recived any treatment for their OSCC prior to the sampling. In the saliva samples 14 biomarkers stood out, 8 of which was up regulated and the remaining 6 were down regulated in comparison to the saliva samples from the healthy controls. Up regulated biomarkers: lactic acid, hydroxyphenyllactic acid, N-nonanoylglycine, 5-hydroxymethyluracil, Succinic acid, Ornithine, Hexanoylcarnitine, Propionylcholine. Down

regulated biomarkers: Carnitine, 4-hydroxy-L-glutamic acid, Acetylphenylalanine,

Sphinganine, Phytosphingosine, S-carboxymethyl-L-cysteine. The saliva was analysed using reversed phase liquid chromatography and hydrophilic interaction chromatography combining with time of flight mass spectrometer (Wang et al., 2014b).

Blood sampling

Oral cancer screening: serum Raman spectroscopic approach

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the same method. Blood samples were collected from 328 patients. The serum samples were analyzed using the serum Raman spectroscopy (RS), looking at the presence of contributions mainly from amino acids, beta-carotene, DNA, and proteins. The serum Raman spectroscopy had a sensitivity of 64 % and a specificity of 80 % (Sahu et al., 2015).

Narrow-band imaging

Effectiveness of narrow band imaging in patients with oral squamous cell carcinoma after treatment.

The purpose of this study was to evaluate the effectiveness of narrow-band imaging (NBI) for detecting OPMD’s and OSCC at an early stage. 101 patients, all previously treated for OSCC, was examined first with a complete head and neck examination with conventional white light, then with the NBI system. To diagnose a lesion as malignant with the NBI system, a well-demarcated brownish area with thick dark spots and/or winding vessels had to be present. The narrow band imaging examination had a sensitivity of 95 % and a specificity of 97 % (Chu et

al., 2012).

DISCUSSION

Summery of review results

19 studies were included in the review, 6 general categories of diagnostic test methods were identified, and a wide array of specific analysis methods within the 6 general categories, this made the studies heterogenic and not appropriate for combining quantitative diagnostic accuracy results. Diagnostic accuracy was specified in all included studies, almost exclusively through sensitivity and specificity. Studies were carried out in countries all over the world, most often in a public healthcare setting. Methodological quality differed between studies, commonplace was failure to report on specifics like time delay between index and reference test e.g. Wang et al., 2014a, Wang et al., 2014b, Sahu 2015 et al., Chu 2012 et al.. Some studies had very thorough methodological quality e.g. Paderni et al., 2011, Rana et al., 2012, Hanken

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24 Evidence strength of review findings

We used the QUADAS assessment tool in order to grade each study concerning different kinds of biases and methodological shortcomings. The QUADAS assessment tool is a widely recognized, detailed, user friendly and also used by the Swedish agency for health technology

assessment and assessment of social services (SBU). This adds strength to the review and some

credence to the findings of the present review. The low number of included studies (19) and some methodological flaws reduces evidence strength for most categories i.e. Blood sampling,

saliva sampling, narrow-band imaging and metachromatic dye staining.

However, in the category of Brush biopsy sampling, 10 studies were included and as a whole this category were judged to have decent scientific methodology and a reasonable risk of bias.

Tissue autofluorescence category included 4 studies of which 3 studies were judged as low risk

of bias and had quite comparable study design, and with a total of 2453 participants.

Conclusion

From the findings and evidence presented in this review we conclude that the Brush biopsy

sampling category has the strongest case to be considered as an accurate, effective and practical

diagnostic test for early detection of potentially malignant oral lesions and oral squamous cell carcinoma. This conclusion is based on evidence strength, the large body of evidence and methodological soundness. As for diagnostic accuracy, the Brush biopsy sampling category generally reported high degrees of sensitivity and specificity. As an alternative or possible adjunctive early detection method, we cautiously suggest Tissue autofluorescence. In spite of the rather shallow body of evidence, we consider the results of the assessed studies to show some promise.

Further research

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Further research could focus on more homologous studies in order to provide pooling of results as a solid foundation for use of statistical Meta-Analysis tools. Furthermore the RCT study design, preferably blinded, will provide solidity to the evidence strength of future reviews.

ACKNOWLEDGMENTS

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