What is the diagnostic accuracy of reflectance confocal microscopy for the detection of basal or squamous cell carcinoma of the skin in adults?

What is the aim of the review?

The aim of this Cochrane Review was to find out how accurate reflectance confocal microscopy (RCM) is on its own or compared to inspection of a skin lesion with the naked eye alone or using a hand-held microscope called dermoscopy for diagnosing two common forms of keratinocyte skin cancer: basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) in adults. Review authors in Cochrane included 10 studies to answer this question.

Why is improving the diagnosis of BCC or cSCC important?

There are a number of different types of skin cancer. BCC and cSCC are usually localised skin cancers. Making the correct diagnosis is important because mistaking one skin cancer for another can lead to the wrong treatment being used or lead to a delay in effective treatment. A missed diagnosis of BCC (known as a false-negative result) can result in the missed BCC growing and causing disfigurement. A missed diagnosis of cSCC is more serious as it could spread to other parts of the body. Diagnosing a skin cancer when it is not actually present (a false-positive result) may result in unnecessary biopsy or treatment and can cause discomfort and worry to patients.

What was studied in the review?

Microscopic techniques are used by skin cancer specialists to provide a more detailed, magnified examination of suspicious skin lesions than can be achieved using the naked eye alone. Currently, dermoscopy is used by doctors as part of the examination of suspicious skin lesions. RCM is a new microscopic technique to increase the magnification. It is a hand-held device or static unit using infrared light that can visualise deeper layers of the skin when compared with dermoscopy. Both techniques are painless procedures, but RCM is more expensive, time consuming, and requires additional specialised training. Dermoscopy can be used by general practitioners (GP) whereas RCM is likely to only be used by hospital specialists for people who have been referred with a skin lesion that is suspected to be a skin cancer. We wanted to see if RCM should be used instead of, or as well as, inspection of a skin lesion with the naked eye alone or using dermoscopy to diagnose BCC or cSCC. The accuracy of the test was looked at when used on people with any suspicious skin lesion and also in people with skin lesions that were tricky to diagnose.

What are the main results of the review?

We found 10 studies that included information on 11 groups of people with lesions suspicious for skin cancer. The main results were based on seven of the 11 sets of data: four in any lesion suspicious for skin cancer and three in particularly difficult to diagnose skin lesions.

For the comparison of RCM versus dermoscopy, we found four sets of data that included 912 suspicious skin lesions. The results suggested that in a group of 1000 people with any suspicious lesion, of whom 125 (12.5%) really do have BCC:

- an estimated 139 people will have an RCM result indicating BCC is present;

- of these, 44 (32%) people will not have BCC (false-positive results) including one person with a melanoma mistaken for a BCC;

- of the 861 people with an RCM result indicating that BCC is not present, 30 (3%) will actually have BCC.

The review also included three sets of data on people that had 668 particularly difficult to diagnose skin lesions, one comparing RCM to dermoscopy. The results suggested that if RCM was to be used by skin specialists in a group of 1000 people, of whom 150 (15%) really do have BCC:

- an estimated 269 people will have an RCM result indicating BCC is present;

- of these, 128 (48%) people will not have a BCC (known as a false-positive result), including as many as 19 people with melanomas mistaken for BCCs;

- of the 732 people with an RCM result indicating that BCC is not present, nine (1%) will actually have BCC.

There was not enough evidence to determine the accuracy of RCM for the detection of cSCC in either population group.

How reliable are the results of this review?

There was a lot of variation in the results of the studies in this review. Poor reporting of study conduct made assessment of the reliability of studies difficult. It was unclear whether studies were representative of populations eligible for testing with RCM, and test interpretation was often undertaken using images, remotely from the patient and the interpreter blinded to clinical information that would normally be available in practice. Only one study compared the accuracy of dermoscopy and RCM. Most studies were conducted by specialist research teams with high levels of training and experience with RCM, meaning that RCM may appear better than it would be when used in everyday practice. Most studies reported diagnosis based on observers' subjective views, which might not be the same for people using the technique in everyday practice. In nine studies, the diagnosis of skin cancer was made by a skin biopsy or by following up those people over time to make sure they remained negative for skin cancer*. This is likely to have been a reliable method for deciding whether patients really had skin cancer. In one study, the absence of skin cancer was made by experts looking at the skin, a method that may be less reliable for deciding whether patients really had skin cancer.

Who do the results of this review apply to?

Five studies were carried out in Europe (61%), and the rest in Asia, Oceania, North America, or more than one continent. The average ages of people who took part ranged from 41 to 65 years. The percentage of people with BCC in these studies ranged from 6% to 83% (a middle value of 12% for any suspicious lesion and 15% for difficult to diagnose skin lesions). For studies of RCM used for cSCC, the percentage of people with cSCC ranged between 4% and 13%. In many studies it was not clear what tests people taking part had received before RCM.

What are the implications of this review?

There was not enough good evidence to support the use of RCM for the diagnosis of BCC or cSCC outside of research studies. There was a lot of variation and uncertainty in results and in the ways studies were carried out, reducing the reliability of findings. Using RCM might avoid the need for a diagnostic biopsy in people who see a doctor with a high suspicion of a BCC lesion, but more research is needed to confirm this. Such research should compare RCM to dermoscopy in well-described groups of people with suspicious skin lesions and they must say whether other skin cancers end up being missed or being wrongly classified as BCC.

How up-to-date is this review?

The review authors searched for and used studies published up to August 2016.

*In these studies, biopsy or clinical follow-up were the reference standards (means of establishing final diagnoses).

Authors' conclusions: 

There is insufficient evidence for the use of RCM for the diagnosis of BCC or cSCC in either population group. A possible role for RCM in clinical practice is as a tool to avoid diagnostic biopsies in lesions with a relatively high clinical suspicion of BCC. The potential for, and consequences of, misclassification of other skin cancers such as melanoma as BCCs requires further research. Importantly, data are lacking that compare RCM to standard clinical practice (with or without dermoscopy).

Read the full abstract...
Background: 

Early accurate detection of all skin cancer types is important to guide appropriate management and improve morbidity and survival. Basal cell carcinoma (BCC) is usually a localised skin cancer but with potential to infiltrate and damage surrounding tissue, whereas cutaneous squamous cell carcinoma (cSCC) and melanoma are higher risk skin cancers with the potential to metastasise and ultimately lead to death. When used in conjunction with clinical or dermoscopic suspicion of malignancy, or both, reflectance confocal microscopy (RCM) may help to identify cancers eligible for non-surgical treatment without the need for a diagnostic biopsy, particularly in people with suspected BCC. Any potential benefit must be balanced against the risk of any misdiagnoses.

Objectives: 

To determine the diagnostic accuracy of RCM for the detection of BCC, cSCC, or any skin cancer in adults with any suspicious lesion and lesions that are difficult to diagnose (equivocal); and to compare its accuracy with that of usual practice (visual inspection or dermoscopy, or both).

Search strategy: 

We undertook a comprehensive search of the following databases from inception to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.

Selection criteria: 

Studies of any design that evaluated the accuracy of RCM alone, or RCM in comparison to visual inspection or dermoscopy, or both, in adults with lesions suspicious for skin cancer compared with a reference standard of either histological confirmation or clinical follow-up, or both.

Data collection and analysis: 

Two review authors independently extracted data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities using the bivariate hierarchical model. For computation of likely numbers of true-positive, false-positive, false-negative, and true-negative findings in the 'Summary of findings' tables, we applied summary sensitivity and specificity estimates to lower quartile, median and upper quartiles of the prevalence observed in the study groups. We also investigated the impact of observer experience.

Main results: 

The review included 10 studies reporting on 11 study cohorts. All 11 cohorts reported data for the detection of BCC, including 2037 lesions (464 with BCC); and four cohorts reported data for the detection of cSCC, including 834 lesions (71 with cSCC). Only one study also reported data for the detection of BCC or cSCC using dermoscopy, limiting comparisons between RCM and dermoscopy. Studies were at high or unclear risk of bias across almost all methodological quality domains, and were of high or unclear concern regarding applicability of the evidence. Selective participant recruitment, unclear blinding of the reference test, and exclusions due to image quality or technical difficulties were observed. It was unclear whether studies were representative of populations eligible for testing with RCM, and test interpretation was often undertaken using images, remotely from the participant and the interpreter blinded to clinical information that would normally be available in practice.

Meta-analysis found RCM to be more sensitive but less specific for the detection of BCC in studies of participants with equivocal lesions (sensitivity 94%, 95% confidence interval (CI) 79% to 98%; specificity 85%, 95% CI 72% to 92%; 3 studies) compared to studies that included any suspicious lesion (sensitivity 76%, 95% CI 45% to 92%; specificity 95%, 95% CI 66% to 99%; 4 studies), although CIs were wide. At the median prevalence of disease of 12.5% observed in studies including any suspicious lesion, applying these results to a hypothetical population of 1000 lesions results in 30 BCCs missed with 44 false-positive results (lesions misdiagnosed as BCCs). At the median prevalence of disease of 15% observed in studies of equivocal lesions, nine BCCs would be missed with 128 false-positive results in a population of 1000 lesions. Across both sets of studies, up to 15% of these false-positive lesions were observed to be melanomas mistaken for BCCs. There was some suggestion of higher sensitivities in studies with more experienced observers. Summary sensitivity and specificity could not be estimated for the detection of cSCC due to paucity of data.

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