University of Birmingham Systematic review of diagnostic accuracy of reflectance confocal microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions

Background: Melanoma is a cancer of the skin and is increasing in incidence in the UK and Europe. Melanoma is a condition that is often curable if detected at an early stage, which makes accurate diagnosis vital. Reflectance confocal microscopy (RCM) is a tool used to image the skin. It gives high mag-nification images of the skin, which may provide more accurate diagnosis of lesions that are equivocal on clinical examination and for the other databases as The searches were performed from database inception. The search was conducted by two independent reviewers. of the reference lists of the review articles and studies included in the final

the 1990's. The devices are now small and ergonomically able to image most areas of the skin. The diagnostic features are easy to learn and reproducible [13,16]. The devices themselves are quite, they are in limited use in clinical practice [17] and combined with the time to assess each lesion, may restrict the use to specialist clinics.
A comprehensive search found no systematic reviews or meta-analysis. Systematic reviews are important as they allow for a more transparent and objective appraisal of the evidence.
Meta-analysis where appropriate can enhance the precision of the estimates of individual studies [18]. The objective for this review is to examine the diagnostic accuracy of RCM in the diagnosis of melanoma as an add-on test for lesions that are clinically and/or dermoscopically equivocal/suspicious for melanoma in cohort studies that have used a predefined threshold. This must be a pre-defined scoring system or system of diagnosis but there is no restriction on the system. Metaanalysis will be conducted if there is sufficient consistency between studies in the way the thresholds are applied.

Search strategy
Electronic searches were conducted of Medline, Embase, CINAHL, the Cochrane Register of Diagnostic Test Accu-   [3].
Prognosis for melanoma is very much dependent on the stage of the disease when it is diagnosed so early accurate diagnosis of melanoma is crucial. The five-year survival for stage 1A melanoma is 97%. The five-year survival drops rapidly to 10-15% for stage 4 metastatic disease [4]. This rapid decline in survival with higher stage is because the only potentially curative treatment is surgical excision [5]. Adjuvant therapy for non-metastatic melanoma has not yet been demonstrated to provide a survival benefit [6] and no therapy has proven to extend survival for metastatic melanoma [7,8].
The currently accepted best diagnostic method for melanoma is dermoscopy [9].
A recent meta-analysis of dermoscopy in the diagnosis of melanoma pooled the sensitivities and specificities and found a sensitivity of 91% and a specificity of 86% [10]. Most dermoscopy research has been conducted in white skinned populations however there is some evidence of the ability of dermoscopy to work equally well in non-white populations [11].
Reflectance confocal microscopy (RCM) also known as confocal laser scanning microscopy (CLSM) of the skin was first described in the early 1990s [12]. This technology uses a near infrared laser to obtain images of the top layers of the skin. These images are magnified such that they are "quasihistological." From the images, information can be obtained regarding cell structure and the architecture of the surrounding tissues. The images are analyzed and combinations of features are assessed to give a positive or negative diagnosis of melanoma. Several criteria have been developed to analyze images of RCM [13]. The test itself takes about ten minutes for imaging and evaluation of a skin lesion.
The goal of diagnosing melanoma is to correctly identify melanomas, while at the same time, excising as few benign lesions as possible. The most appropriate first line examination for this is dermoscopy, which has been shown to be a more accurate diagnostic tool than unaided eye examination [9]. Given the time needed to use RCM, it is most appropriate as a secondary examination add test to dermoscopy for lesions where dermoscopy does not give a confident diagnosis. This role has been suggested previously [14,15].
There have been many narrative reviews on the use of RCM in the diagnosis of melanoma. These articles have focused mainly on describing the technology and discussing its potential role in melanoma diagnosis. RCM technology has advanced since the first instruments were introduced in

Assessment of methodological quality
Two authors independently assessed methodological quality of the studies using the QUADAS-2 tool [23]. Any disagreements were resolved by discussion. The results of the quality assessment are presented with a textural methodological quality summary and graphical representation.

Search
The search of the databases was conducted on February 8, 2012. After screening for duplicates 951 studies were examined. A flow diagram of the search can be found in Figure 1.
After examining titles and abstracts the full text of 39 articles were retrieved. There were five articles that met the inclusion criteria. These are shown in Table 1.

Excluded studies
There were five studies, which were derivation studies, or studies that did not validate on a new set of patients.
There were 15 descriptive correlation studies, which only described which RCM features were associated with melanoma. There were four case reports or small case series, two narrative review articles, one editorial and one study looking at observer agreement of the RCM features associated with melanoma.

Methodological quality assessment
The exclusion criteria for studies in the review included two major methodological quality criteria. The studies could not be case control studies nor could they be studies that set a diagnostic threshold i.e.: studies that developed a scoring system. Case control studies have been demonstrated to overestimate diagnostic accuracy when compared to cohort studies that use an appropriate spectrum [24]. Studies that derive/set a threshold use multivariable analysis to derive a score. These scores are derived on a certain population. It is very often the case that these scoring systems perform worse when they are validated in another population, however similar [25].
This resulted in a low risk of bias regarding the applicability of the included patients and the appropriateness of the index test. In this study, the reporting of patient selection was generally poor however all domains were graded as low risk of bias. The methodological quality assessment is shown graphically in Table 2.

Findings
Five studies were identified comprising 909 lesions. The average prevalence of melanoma was 36.2% with a range from 29-39. Three studies used the RCM diagnostic scor-

Type of study
Cohort studies of diagnostic test accuracy with a predefined threshold that was established on separate data are eligible for inclusion.

Target condition
Melanoma of the skin.

Study population
Patients presenting with lesions suspicious for melanoma that were equivocal to clinical and dermoscopic diagnosis. No restriction was placed upon participant characteristics such as age, sex, ethnicity etc.

Index test
Reflectance confocal microscopy. There was no restriction on the type of algorithm or diagnostic process.

Reference standard
Histopathology of the excised skin lesion or long-term clinical follow-up.

Data extraction and management
Per lesion data was extracted onto a study specific data extraction sheet by two authors independently. The following data was collected: the details of the study population, details of the reference standard and index test, blinding of the reference standard and the index test. Prevalence of melanoma, information to complete the 2 x 2 table.

Statistical analysis and data synthesis
Data were extracted by two reviewers independently. Hierarchical bivariate random-effects meta-analysis [19] was used to perform the statistical meta-analysis as this has been demonstrated to be the most robust method [19].
If there appeared to be no or minimal threshold differences between the studies clinically or on the receiver operator characteristic (ROC) plot then a summary statistic in the form of sensitivity and specificity was planned [20]. If there were, clinically and visually, the appearance of a threshold effect then the summary ROC curve was planned as the most appropriate summary measure [20].
If a study presented several sensitivity and specificity estimates on a receiver operator characteristic curve (ROC) then the point estimate used for meta-analysis was the point chosen by the author of the article.
The results are presented graphically using RevMan5 [21]. The studies were combined in a statistical meta-analysis using the METANDI function in STATA [22].  The purpose of this review was to evaluate RCM as an add-on test to existing diagnostic pathways, not to evaluate it as a replacement test. It has been suggested that RCM is more sensitive than dermoscopy [13]. If all lesions that were suspicious to the unaided eye examination were examined Given the low number of studies included in the review, statistical subgroup analysis and covariate hierarchical modeling for investigation of heterogeneity were not performed due to low statistical power.

Discussion
When examining the use of a new diagnostic test it is important to consider whether its introduction will improve    These factors combined with the concept that diagnostic accuracy determined from laboratory condition studies may be different from the diagnostic accuracy in the real life clinical setting [31], mean that the external validity of these results has to be taken cautiously. in the images obtained. A study looking at the agreement between observers in identifying these features found high overall levels of reproducibility [16].

Summary
Reflectance confocal microscopy may contribute to the diagnosis of melanoma as an add-on test in the diagnostic pathway to reduce over-diagnosis following dermoscopy. Reduction in the excision rate of benign lesions that look suspicious on clinical examination may be important particularly where treatment by removal is potentially difficult or harmful. As no diagnostic test is 100% accurate, each clinician and patient will have to decide if the trade off between missing a small number of melanomas is worth the reduction in excision of benign lesions.