What was the aim of the review?
The aim of this Cochrane Review was to find out how accurate reflectance confocal microscopy (RCM) was on its own and used in addition to dermoscopy compared to dermoscopy alone for diagnosing melanoma. Review authors in Cochrane included 18 publications to answer this question.
Why is improving the diagnosis of melanoma important?
Melanoma is one of the most dangerous forms of skin cancer. Not recognising a melanoma when it is present (called a false negative test result) delays surgery to remove it, risking cancer spreading to other parts in the body and possibly death. Diagnosing a skin lesion as a melanoma when it is not present (called a false positive result) may result in unnecessary surgery, further investigations, and patient anxiety.
What did the review study?
Microscopic techniques are used by skin cancer specialists to allow a more detailed, magnified examination of suspicious skin lesions than can be achieved using the naked eye alone. Currently, dermoscopy (a handheld device using natural light) can be used as part of the clinical examination of suspicious skin lesions. RCM is a new microscopic technique (a handheld device or static unit using infrared light) that can visualise deeper layers of the skin compared to dermoscopy. Both techniques are painless procedures, but RCM is more expensive, time consuming, and requires additional training. Dermoscopy can be used by general practitioners whereas RCM is likely to only be used by secondary care specialists in people who have been referred with a lesion suspicious for skin cancer. We sought to find out whether RCM should be used instead of, or in addition to, dermoscopy, to diagnose melanoma in any suspicious skin lesion or only in particularly difficult to diagnose skin lesions.
What were the main results of the review?
The review included 18 publications reporting data for 19 groups of participants with lesions suspected of melanoma. The main results were based on 16 of the 19 datasets (sets of information and results).
The review included nine datasets with 1452 lesions in people with any suspicious skin lesion, three of which compared RCM to dermoscopy. The results suggested that in 1000 lesions, of which 300 (30%) actually are melanoma:
- an estimated 396 would have an RCM result indicating melanoma was present, and of these, 126 (32%) would not be melanoma (false positive results);
- in the same group of 1000 lesions, dermoscopy would produce 406 false positive results, meaning RCM would avoid unnecessary surgery in 280 lesions compared to dermoscopy;
- of the 604 lesions with an RCM result indicating that melanoma was not present (and 324 lesions with a dermoscopy result indicating that melanoma was not present), 30 would actually be melanoma (false negative results). This equated to a false negative rate of 5% for RCM and 9% for dermoscopy.
The review also included seven datasets with 1177 lesions in people with particularly difficult to diagnose skin lesions, three of which compared RCM to dermoscopy. The results suggested that if skin specialists used RCM in a group of 1000 lesions, of which 200 (20%) were actually melanoma:
- an estimated 292 would have an RCM result indicating melanoma was present, and of these, 112 (38%) would not be melanoma (false positive results);
- in the same group of 1000 lesions, dermoscopy would produce 408 false positive results, meaning RCM would avoid unnecessary surgery in 296 lesions compared to dermoscopy;
- of the 708 lesions with an RCM result indicating that melanoma was not present (and 412 lesions with a dermoscopy result indicating that melanoma was not present), 20 would actually have melanoma (false negative results). This equates to a false negative rate of 3% for RCM and 5% for dermoscopy.
How reliable were the results of the studies of this review?
In all included studies, the diagnosis of melanoma was made by lesion biopsy (RCM/dermoscopy positive) (a biopsy involves taking a sample of body cells and examining them under a microscope), and the absence of melanoma was confirmed by biopsy or by follow-up over time to make sure the skin lesion remained negative for melanoma (RCM/dermoscopy negative)*. This is likely to have been a reliable method for deciding whether people really had melanoma. Only a small number of studies compared the accuracy of dermoscopy and RCM. Most were conducted by specialist research teams with high levels of experience with RCM. Therefore, RCM may have appeared more accurate than it actually was. Participants in the nine studies of any suspicious lesion may have had very obvious disease compared to that seen in practice leading to a lower number of false positive results than would actually occur. It is not possible to recommend a definition of a positive RCM test that will reliably produce the results presented here due to differences between studies.
Who do the results of this review apply to?
Eleven studies were undertaken in Europe (61%), with the remainder undertaken in Oceania, North America, or more than one continent. Mean age ranged from 39 to 54.7 years. The percentage of people with melanoma ranged between 1.9% and 41.5% (a median (midpoint reading) of 19% for difficult to diagnose skin lesions and 32% for any suspicious lesion). The majority of studies only included people with certain types of skin lesion. In many studies, it was not clear what tests participants had received before RCM.
What are the implications of this review?
RCM appears to be an accurate test for identifying melanoma, and it may reduce the number of people receiving unnecessary surgery by up to three-quarters compared to dermoscopy. There is considerable variation and uncertainty in results and in study conduct, reducing the reliability of findings. Use of RCM may be of most benefit in people with particularly difficult to diagnose lesions rather than people with any lesion suspicious for melanoma. Further research comparing RCM and dermoscopy in well described groups of people with difficult to diagnose skin lesions is needed.
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).
RCM may have a potential role in clinical practice, particularly for the assessment of lesions that are difficult to diagnose using visual inspection and dermoscopy alone, where the evidence suggests that RCM may be both more sensitive and specific in comparison to dermoscopy. Given the paucity of data to allow comparison with dermoscopy, the results presented require further confirmation in prospective studies comparing RCM with dermoscopy in a real-world setting in a representative population.
Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Early detection and treatment is key to improving survival; however, anxiety around missing early cases needs to be balanced against appropriate levels of referral and excision of benign lesions. Used in conjunction with clinical or dermoscopic suspicion of malignancy, or both, reflectance confocal microscopy (RCM) may reduce unnecessary excisions without missing melanoma cases.
To determine the diagnostic accuracy of reflectance confocal microscopy for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults with any lesion suspicious for melanoma and lesions that are difficult to diagnose, and to compare its accuracy with that of dermoscopy.
We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; and seven other databases. We studied reference lists and published systematic review articles.
Studies of any design that evaluated RCM alone, or RCM in comparison to dermoscopy, in adults with lesions suspicious for melanoma or atypical intraepidermal melanocytic variants, compared with a reference standard of either histological confirmation or clinical follow-up.
Two review authors independently extracted all 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 per algorithm and threshold using the bivariate hierarchical model. To compare RCM with dermoscopy, we grouped studies by population (defined by difficulty of lesion diagnosis) and combined data using hierarchical summary receiver operating characteristic (SROC) methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of specificity at the point on the SROC curve with 90% sensitivity as this value lies within the estimates for the majority of analyses. We investigated the impact of using a purposely developed RCM algorithm and in-person test interpretation.
The search identified 18 publications reporting on 19 study cohorts with 2838 lesions (including 658 with melanoma), which provided 67 datasets for RCM and seven for dermoscopy. Studies were generally at high or unclear risk of bias across almost all domains and of high or unclear concern regarding applicability of the evidence. Selective participant recruitment, lack of blinding of the reference test to the RCM result, and differential verification were particularly problematic. Studies may not be representative of populations eligible for RCM, and test interpretation was often undertaken remotely from the patient and blinded to clinical information.
Meta-analysis found RCM to be more accurate than dermoscopy in studies of participants with any lesion suspicious for melanoma and in participants with lesions that were more difficult to diagnose (equivocal lesion populations). Assuming a fixed sensitivity of 90% for both tests, specificities were 82% for RCM and 42% for dermoscopy for any lesion suspicious for melanoma (9 RCM datasets; 1452 lesions and 370 melanomas). For a hypothetical population of 1000 lesions at the median observed melanoma prevalence of 30%, this equated to a reduction in unnecessary excisions with RCM of 280 compared to dermoscopy, with 30 melanomas missed by both tests. For studies in equivocal lesions, specificities of 86% would be observed for RCM and 49% for dermoscopy (7 RCM datasets; 1177 lesions and 180 melanomas). At the median observed melanoma prevalence of 20%, this reduced unnecessary excisions by 296 with RCM compared with dermoscopy, with 20 melanomas missed by both tests. Across all populations, algorithms and thresholds assessed, the sensitivity and specificity of the Pellacani RCM score at a threshold of three or greater were estimated at 92% (95% confidence interval (CI) 87 to 95) for RCM and 72% (95% CI 62 to 81) for dermoscopy.