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. 2017 Mar 13;143(9):1627–1635. doi: 10.1007/s00432-017-2391-9

Comparison of dermoscopy and reflectance confocal microscopy for the diagnosis of malignant skin tumours: a meta-analysis

Yi-Quan Xiong 1, Shu-Juan Ma 2, Yun Mo 1, Shu-Ting Huo 1, Yu-Qi Wen 1, Qing Chen 1,✉
PMCID: PMC11818986  PMID: 28289898

Abstract

Purpose

Dermoscopy and reflectance confocal microscopy (RCM) are non-invasive methods for diagnosis of malignant skin tumours. The aim of this study was to compare the accuracy of dermoscopy and RCM for the diagnosis of malignant skin tumours.

Methods

Systematic electronic literature searches were conducted to include PubMed, Medline, Embase, the Cochrane Library database, and Web of Science, up to 26 April 2016. Pooled additional detection rate (ADR), diagnostic accuracy, and 95% confidence intervals (CIs) were calculated using STATA and Meta-Disc analysis.

Results

Eight published studies were included in the analysis, involving 1141 skin lesions, which reported a per-lesion analysis of dermoscopy and RCM. Within the same patient group and at the per-lesion level, RCM significantly increased the detection rate of malignant skin tumours by 7.7% (95% CI 0.01–0.14). The pooled sensitivity of dermoscopy was similar to RCM [88.1% (95% CI 0.85–0.91) vs. 93.5% (95% CI 0.91–0.96)]. The specificity of dermoscopy was significantly lower than that of RCM [52.9% (95% CI 0.49–0.57) vs. 80.3% (95% CI 0.77–0.83)]. The pooled ADR of RCM for melanoma detection was 4.3% (95% CI 0.002–0.08). Pooled sensitivity and specificity of dermoscopy for melanoma detection were 88.4% (95% CI 0.84–0.92) and 49.1% (95% CI 0.45–0.53), respectively. The pooled sensitivity and specificity of RCM were 93.5% (95% CI 0.90–0.96) and 78.8% (95% CI 0.75–0.82), respectively.

Conclusions

When compared with dermoscopy, RCM has a significantly greater diagnostic specificity for malignant skin tumours and so could improve their detection rate.

Keywords: Skin cancer, Melanoma, Dermoscopy, Reflectance confocal microscopy, Meta-analysis

Introduction

Worldwide, the increasing incidence of malignant skin tumours and their persistently high mortality rates, including melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC), have been observed in recent decades (Birch-Johansen et al. 2010; de Vries and Coebergh 2004; Trakatelli et al. 2007). Early diagnosis of malignant skin tumours is crucial to the improvement of patient survival, as delayed diagnosis may lead to local invasion and tumour metastasis. For example, for melanoma, although the 5-year overall survival rate for Stage I melanoma is more than 90% and 5-year survival falls to 10–15% for Stage IV melanoma, with surgical excision being the main curative treatment option (Balch et al. 2009).

Dermoscopy, also known as dermatoscopy or epiluminescence microscopy (ELM), is a non-invasive technique that uses a microscope to enable sub-surface structures of the skin to be accessible to visual examination. The previous studies have demonstrated that dermoscopy can improve the clinical diagnosis of pigmented lesions including early melanoma (Argenziano et al. 2006; Bono et al. 2002; Dummer et al. 1993). A meta-analysis included 8487 suspicious skin lesions and showed that the sensitivity and specificity of dermoscopy in the diagnosis of melanoma were both 90% (Vestergaard et al. 2008). Dermoscopy has successfully been introduced in routine screening for malignant skin tumours, and currently, it has widespread clinical use (Menzies and Zalaudek 2006).

In current clinical dermatology practice, several adjunctive diagnostic methods are now used, including reflectance confocal microscopy (RCM), also known as confocal laser scanning microscopy (CLSM), and also the method of optical coherence tomography (OCT) (Mogensen et al. 2009; Rajadhyaksha et al. 1995). RCM is an optical imaging technique with high resolution, which allows the examination of the epidermis and papillary dermis at almost a cellular resolution. RCM technology has widely been used in the diagnosis, surveillance, and therapy of malignant skin tumours, and can also be used to guide Moh’s micrographic surgery without frozen-section histopathology (Ahlgrimm-Siess et al. 2009; Gonzalez 2008; Rajadhyaksha et al. 2001). RCM has been reported to show excellent performance for the detection of malignant skin tumours, including melanoma, BCC, SCC, and lentigo maligna (Gerger et al. 2005; Longo et al. 2013; Nori et al. 2004). A recent meta-analysis showed that the pooled sensitivity and specificity of RCM for the diagnosis of malignant skin tumours were 93.6 and 82.7%, respectively (Xiong et al. 2016a).

There is now a clinical consensus that both RCM and dermoscopy can improve the diagnosis accuracy of visual skin examination when compared with naked-eye examination alone. Based on the previous meta-analysis data (Vestergaard et al. 2008; Xiong et al. 2016a), the diagnostic accuracy of both dermoscopy and RCM appears to be comparable. However, the previous systematic reviews and meta-analysis have included varied study populations, inclusion criteria, data extraction, and statistical analysis, all of which may introduce bias when directly comparing the two diagnostic techniques. There is still need to clarify whether or not RCM is a superior diagnostic technique to dermoscopy to reduce the rate of unnecessary surgical skin excisions for patients. For these reasons, a systematic literature review and meta-analysis were performed to determine the accuracy of within-patient comparisons between dermoscopy and RCM for the diagnosis of malignant skin tumours.

Methods

Meta-analysis of the diagnostic value of dermoscopy and RCM in malignant tumours of the skin was conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) (Moher et al. 2009).

Literature search

Systematic electronic literature searches were conducted of the following databases: PubMed, Medline, Embase, Cochrane Library database, and Web of Science. Literature searches were performed up to 26th April 2016.

The following keywords were used, separately and in combination: “reflectance confocal microscopy,” “confocal laser scanning microscopy,” “RCM,” “CLSM,” “dermoscopy,” “dermatoscopy,” “dermoscopic,” “skin,” “cancer,” “tumour,” “melanoma,” “basal cell carcinoma,” “squamous cell carcinoma,” “BCC,” and “SCC.” The search was restricted to studies on humans, and there was no language restriction. Manual searches were also conducted of the reference lists of review articles and the studies included in the final publication selection.

Inclusion and exclusion criteria

Studies were included if they met following criteria: (1) the evaluation of the additional detection rate (ADR) and/or diagnosis accuracy of dermoscopy and RCM for detection of malignant skin tumours; (2) the comparison groups of dermoscopy and RCM; (3) the reported sensitivity and specificity for both dermoscopy and RCM at a per-patient and/or per-lesion level (a lesion was defined as a biopsy specimen or a biopsy location); (4) the use of biopsy and histology as the standard diagnostic criterion for malignant skin tumours.

Studies were excluded for the following reasons: (1) review articles, editorials, opinions, or case reports; (2) publications that only evaluated the ADR and/or the diagnostic accuracy of dermoscopy or RCM; (3) publications without sufficient data of ADR and/or diagnosis accuracy.

Data selection and extraction

Citations were merged in Endnote (version X7) to facilitate management and data extraction. Two authors applied the inclusion criteria independently to all articles retrieved in an un-blinded standardised manner, and reviewed the publications by title, abstract, and full text. Any disagreement between the two reviewers was resolved by consensus. Data were extracted from each eligible study independently by the two reviewers, including first author, publication year, country of origin, study design, number of enrolled patients, number of lesions, number of dermatologists and their experience, and the sensitivities and specificities of dermoscopy and RCM for detection of malignant skin tumours. The more complete or more recent publications were given precedence if there were multiple publications from the same study or data source.

Quality assessment

The methodological quality of the studies and the risk of bias were independently assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool by two reviewers (Whiting et al. 2011). Any disagreement between the two reviewers was resolved by consensus. QUADAS-2 consists of four key domains that assess patient selection, index test, reference standard, flow of patients through the study and timing of the index tests, and reference standard (flow and timing). The risk of bias was judged as “low,” “unclear,” or “high.”

Statistical analysis

Sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) underwent meta-analysis using Meta-DiSc software, version 1.4 (Clinical Biostatistics Unit, Ramony Cajal Hospital, Madrid, Spain) (Zamora et al. 2006). A weighted symmetric summary receiver-operating curve (ROC) was drawn, and the area under the curve (AUC) was calculated (Moses et al. 1993). Between-study heterogeneity was estimated by the I 2 statistic and a significant heterogeneity was defined as I 2 ≥ 50%. Pooled results and corresponding 95% confidence intervals (CI) were calculated with a fixed-effects model (Mantel and Haenszel method) when heterogeneity was not significant (I 2 < 50%); otherwise, a random-effects model (DerSimonian and Laird method) was applied. Threshold analysis was performed using the Spearman coefficient (Spearman coefficient >0.5 with P < 0.05) (DerSimonian and Laird 1986). Pooled ADR and publication bias were assessed using STATA, version 12.0 (Stata Corp LP, College Station, TX, USA). The ADR was defined as the additional number of RCM-detected malignant skin tumours divided by the total number of dermoscopy-detected and RCM-detected malignant skin tumours. Forest plots were constructed for visual display of pooled results. Deek’s Funnel Plot Asymmetry Test was performed for the assessment of potential publication bias.

Results

Description of the studies included

The systematic literature searches identified 266 potentially relevant studies. Most ineligible studies were excluded on the basis of information in the title or abstract. The selection process is shown in Fig. 1. Eight studies (Alarcon et al. 2014; Guitera et al. 2009, 2014; Langley et al. 2007; Moscarella et al. 2013; Stanganelli et al. 2015; Venturini et al. 2013; Witkowski et al. 2016) including 1141 lesions were eligible for analysis in the review. The main characteristics of these studies are described in Table 1. All the eight studies reported the diagnostic accuracy of dermoscopy and RCM for detection of malignant skin tumours at the per-lesion level. Five studies (Alarcon et al. 2014; Guitera et al. 2009; Langley et al. 2007; Stanganelli et al. 2015; Witkowski et al. 2016) reported the performance of dermoscopy and RCM for the detection of melanoma. Three studies (Alarcon et al. 2014; Langley et al. 2007; Venturini et al. 2013) were prospective in design, and the other five studies (Guitera et al. 2009, 2014; Moscarella et al. 2013; Stanganelli et al. 2015; Witkowski et al. 2016) were retrospective.

Fig. 1.

Fig. 1

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Flow diagram of the studies identified in the meta-analysis

Table 1.

Basic characteristics of the eligible studies

Authors Year Country Study design Center (n) Type of skin cancer Patients (n) Age (mean/median) Male (%) Lesions (n)
Alarcon 2014 Spain Prospectively One Melanoma NA 54 51.5 264
Guitera 2009 Italy, Australia Retrospectively Two Melanoma 326 47 (7–90) 54.3 326
Guitera 2014 Spain, Australia Retrospectively Two Lentigo maligna 31 73 (35–89) 25.8 31
Stanganelli 2015 Italy Retrospectively Two Melanoma 70 40 54.3 70
Witkowski 2016 Italy Retrospectively One BCC,melanoma,SCC and other malignan NA NA NA 260
Venturini 2013 Italy Prospectively One BCC 20 59.5 (37–83) 50 20
Langley 2007 Canada Prospectively One Melanoma 125 44.2 (16–84) NA 125
Moscarella 2013 USA, Italy Retrospectively Two Melanoma, BCC,SCC 24 67 (45–87) 75 45
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BCC basal cell carcinoma, SCC squamous cell carcinoma, NA no data available

Quality assessment

The results of the assessment of study quality using QUADAS-2 are shown in Table 2. In general, most of the studies included in our analysis were of high quality. The risk of bias in the patient selection criteria of four studies was scored as “unclear,” as patients with confirmed malignant skin tumours before endoscopy were included in three studies (Guitera et al. 2014; Moscarella et al. 2013; Venturini et al. 2013). Another study included some benign naevi in the analysis to reduce the MM/nevus ratio (Guitera et al. 2009). Some reports of RCM assessed benign naevi that were not excised for histopathological diagnosis in one study (Guitera et al. 2009), and hence scored an “unclear” risk of bias in the flow and timing category.

Table 2.

QUADAS-2 risk of bias assessment

Study Risk of bias Applicability concerns
Patient selection Index test of dermoscopy Index test of RCM Reference standard Flow and timing Patient selection Index test of dermoscopy Index test of RCM Reference standard
Alarcon et al. (2014) Low Low Low Low Low Low Low Low Low
Guitera et al. (2009) Unclear Low Low Low Unclear Low Low Low Low
Guitera et al. (2014) Unclear Low Low Low Low Low Low Low Low
Stanganelli et al. (2015) Low Low Low Low Low Low Low Low Low
Witkowski et al. (2016) Low Low Low Low Low Low Low Low Low
Venturini et al. (2013) Unclear Low Low Low Low Low Low Low Low
Langley et al. (2007) Low Low Low Low Low Low Low Low Low
Moscarella et al. (2013) Unclear Low Low Low Low Low Low Low Low
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Low low risk, High high risk, Unclear unclear risk

Analysis of additional detection rate

Eight studies (Alarcon et al. 2014; Guitera et al. 2014, 2009; Langley et al. 2007; Moscarella et al. 2013; Stanganelli et al. 2015; Venturini et al. 2013; Witkowski et al. 2016) involving 1141 lesions reported a per-lesion analysis of dermoscopy and RCM for the detection of malignant skin tumours. When compared with dermoscopy, the ADR of RCM ranged from − 0.7–40.0%. The pooled result was 7.7% (95% CI 0.01–0.14, I 2 = 55.3%) (Fig. 2). When only considering melanoma, five studies (Alarcon et al. 2014; Guitera et al. 2009; Langley et al. 2007; Stanganelli et al. 2015; Witkowski et al. 2016 ) with a total of 917 lesions were incorporated for analysis. The ADR of RCM ranged from 3.3 to 25.0% and the pooled result was 4.3% (95% CI 0.002–0.08, I 2 = 0.0%) (Fig. 3).

Fig. 2.

Fig. 2

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Forest plot of the pooled additional detection rate (ADR) of reflectance confocal microscopy (RCM) compared to dermoscopy for detection of malignant skin tumours in per-lesion analysis

Fig. 3.

Fig. 3

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Forest plot of the pooled additional detection rate (ADR) of reflectance confocal microscopy (RCM) compared to dermoscopy for detection of melanoma in per-lesion analysis

Diagnostic accuracy at per-lesion level

Eight studies (Alarcon et al. 2014; Guitera et al. 2014, 2009; Langley et al. 2007; Moscarella et al. 2013; Stanganelli et al. 2015; Venturini et al. 2013; Witkowski et al. 2016) involving 1141 lesions reported the diagnostic accuracy of dermoscopy and RCM for the detection of malignant skin tumours at the per-lesion level. The pooled sensitivity and specificity of dermoscopy were 88.1% (95% CI 0.85–0.91, I 2 = 67.5%) (Fig. 4a) and 52.9% (95% CI 0.49–0.57, I 2 = 96.8%) (Fig. 4b), respectively. The pooled PLR and NLR were 2.80 (95% CI 1.69–4.64, I 2 = 95.4%) and 0.27 (95% CI 0.17–0.42, I 2 = 66.8%), respectively. The AUC for sROC was 0.88. The pooled sensitivity and specificity of RCM were 93.5% (95% CI 0.91–0.96, I 2 = 32.8%) (Fig. 5a) and 80.3% (95% CI 0.77–0.83, I 2 = 88.8%) (Fig. 5b), respectively. The pooled PLR and NLR were 5.71 (95% CI 3.38–9.62, I 2 = 86.3%) and 0.08 (95% CI 0.06–0.12, I 2 = 23.3%), respectively. The AUC for the summary ROC was 0.98.

Fig. 4.

Fig. 4

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Forest plot of the pooled sensitivity (a) and specificity (b) of dermoscopy for detection of malignant skin tumours in per-lesion analysis

Fig. 5.

Fig. 5

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Forest plot of the pooled sensitivity (a) and specificity (b) of reflectance confocal microscopy (RCM) for detection of malignant skin tumours in per-lesion analysis

Five studies (Alarcon et al. 2014; Guitera et al. 2009; Langley et al. 2007; Stanganelli et al. 2015; Witkowski et al. 2016) reported the performance of dermoscopy and RCM for detection of melanoma. The pooled sensitivity and specificity of dermoscopy were 88.4% (95% CI 0.84–0.92, I 2 = 66.9%) and 49.1% (95% CI 0.45–0.53, I 2 = 97.4%), respectively. The pooled PLR was 2.01 (95% CI 1.42–2.84, I 2 = 92.2%) and the pooled NLR was 0.31 (95% CI 0.19–0.51, I 2 = 48.6%), respectively. The AUC for summary ROC was 0.82. The pooled sensitivity and specificity of RCM were 93.5% (95% CI 0.90–0.96, I 2 = 60.5%) and 78.8% (95% CI 0.75–0.82, I 2 = 90.5%), respectively. The pooled PLR was 4.56 (95% CI 2.63–7.90, I 2 = 89.9%) and the pooled NLR was 0.09 (95% CI 0.04–0.25, I 2 = 69.9%), respectively. The AUC for the summary ROC was 0.88.

Heterogeneity analysis

The between-study heterogeneity of dermoscopy and RCM in the diagnostic accuracy analysis were explored by meta-regression analysis. In meta-regression analysis, four variables were included: (1) the study design (prospective vs. retrospective); (2) the study centre (single vs. multiple); (3) the tumour category (single vs. multiple); and (4) the number of lesions (≥ 100 vs. <100). The results showed that study centre had a significant influence on heterogeneity for dermoscopy (single vs. multiple, relative diagnostic odds ratio (RDOR) = 0.19, 95% CI 0.07–0.51, P = 0.007) and study design had a significant influence on heterogeneity for RCM (prospective vs. retrospective, RDOR = 0.08, 95% CI 0.01–0.41, P = 0.011).

Publication bias

Deek’s Funnel Plot Asymmetry Test for the assessment of potential publication bias showed no statistically significant publication bias for dermoscopy (P = 0.44) and RCM (P = 0.43) in the detection of malignant skin tumours in per-lesion analysis.

Discussion

To the best of our knowledge, this is the first systematic literature review and meta-analysis on the published evidence on the ADR and diagnostic accuracy of within-patient comparisons between dermoscopy and RCM for the detection of malignant skin tumours. Eight studies, involving 1141 lesions, were included in this review. The results indicated that, when compared with dermoscopy, RCM significantly increased the detection rate of malignant skin tumours by 7.7% at the per-lesion level. The specificity of RCM for the detection of malignant skin tumours and melanoma was significantly greater than for dermoscopy (80.3 vs. 52.9 and 78.8 vs. 49.1%, respectively). The diagnostic sensitivity of RCM was slightly greater than for dermoscopy, although this finding did not reach statistical significance (93.5 vs. 88.1 and 93.5 vs. 88.4%, respectively).

Previously published meta-analysis studies have concluded that dermoscopy is a useful method for improving the accuracy of diagnosis of malignant skin tumours in experimental settings, clinical settings, and family practice (Bafounta et al. 2001; Herschorn 2012; Kittler et al. 2002; Vestergaard et al. 2008). In addition, the diagnostic accuracy of RCM for malignant skin tumours has been reviewed by three previous meta-analysis studies (Kadouch et al. 2015; Stevenson et al. 2013; Xiong et al. 2016a). Considering the aim of this review was to compare the diagnostic performance of dermoscopy and RCM in the same patient groups, we did not summarise all previous studies which evaluating the diagnostic performance of dermoscopy or RCM separately in pooled analysis. The sensitivity and specificity of RCM determined in this study were similar to recently published meta-analysis findings from Xiong and colleagues (Xiong et al. 2016a). Two previously published meta-analysis studies have shown that the pooled sensitivity of dermoscopy for detection of melanoma was 91 and 90% and the corresponding specificities were 86 and 90% (Rajpara et al. 2009; Vestergaard et al. 2008). The pooled sensitivity of dermoscopy in our study was 88.4%, which was similar to these previously reported studies (Rajpara et al. 2009; Vestergaard et al. 2008). However, in this study, we found that the diagnostic specificity for dermoscopy (49.1%) was lower than previously described (Rajpara et al. 2009; Vestergaard et al. 2008). It is possible that the varied clinical presentation of patients and the varied diagnostic experience of the dermatologists in these different studies could influence the pooled specificity of the dermoscopy findings. In addition, this study evaluated the pooled diagnostic accuracy of dermoscopy compared with RCM and, therefore, the findings may not represent the performance of dermoscopy in routine screening for malignant skin tumours.

The experience of the clinical operators could influence the diagnostic accuracy of dermoscopy and RCM, even when using the same diagnostic algorithm. The previous studies have reported that dermoscopy and RCM performed by experts give better results for the diagnosis of pigmented skin lesions than performed by non-experts (Binder et al. 1999; Piccolo et al. 2002). In recent years, computer-aided diagnosis has also been developed, which can be used to diagnose melanocytic skin lesions without the need for expert clinical experience. A meta-analysis that compared the diagnostic accuracy of computer-aided diagnosis and dermoscopy concluded that the two diagnosis methods performed equally well for diagnosis of melanocytic skin lesions (sensitivity 91 vs. 88% and specificity 86 vs. 79%) (Rajpara et al. 2009). Gerger et al. (2008 ) developed a diagnostic algorithm for the classification of melanocytic skin lesions based on a sample of 857 RCM tumour images. The classification algorithm yielded a correct diagnosis in 92.4% of images of benign melanocytic naevi and 97.6% of melanomas in the study (Gerger et al. 2008). Computer-aided diagnosis has been shown to be useful for the diagnosis of malignant skin tumours, which may be an additional diagnostic method for the non-specialist in clinical settings and family practice.

The implications of the findings of this study are that when compared with dermoscopy, RCM may improve the outcome of patients with equivocal skin lesions, reduce unnecessary excisions, and thus impact on the economic burden associated with the management of malignant skin tumours. Alarcon et al. (2014) reported that the number needed to treat (NNT) of RCM, which was calculated as the number of pigmented lesions excised to detect one case of melanoma, was lower than that for dermoscopy in melanoma detection (NNT, 1.12 vs. 3.73, respectively). Guitera et al. (2009) reported that the combination of RCM and dermoscopy achieved a diagnostic sensitivity of 98% in the evaluation of clinically suspicious melanocytic lesions, resulting in a reduction of 23% of excised benign lesions. Recently, a similar finding has been shown for the combination of dermoscopy and RCM in the detection of basal cell carcinoma (BCC), which was reported to have a positive predictive value of 94.6% (Witkowski et al. 2016). Although RCM is a valid method of accurately identifying malignant skin tumours, the technique takes 5–10 min to evaluate a skin lesion, whereas dermoscopy takes seconds, which means that RCM may not be chosen as a first-level examination method (Guitera et al. 2009; Stevenson et al. 2013). It may be possible that RCM could be considered as an adjunctive test to dermoscopy to assist in the management of suspicious lesions in a secondary care setting.

Real-time analysis is the optimum approach to the investigation of the performance of RCM, to reflect the real-world effect of this technique in routine clinical practice. However, we identified only one study in which the diagnostic performance of RCM was evaluated in real-time(Langley et al. 2007), while all other studies were blinded. Diagnostic optical imaging studies of gastrointestinal epithelial lesions have shown that blinded and real-world diagnostic studies can differ in their diagnostic accuracy (Wanders et al. 2013; Xiong et al. 2016b). Therefore, future studies to evaluate the diagnostic accuracy of RCM in real-time are recommended.

This meta-analysis had limitations. There was significant heterogeneity among the studies included. Different inclusion and exclusion criteria, different diagnostic criteria, and different observer experience bias could all contribute to the heterogeneity. Although we performed meta-regression, the result did not identify all of the heterogeneity between studies. Although we used a random-effects model, there were still some non-identified influences on the final results. Partial studies were included in the evaluation, and some of which were low-quality studies, which may have caused some bias in the final statistical results.

In conclusion, the results of this systematic literature review and meta-analysis have shown that, when compared with dermoscopy, RCM has a significantly greater diagnostic specificity for malignant skin tumours and so could improve their detection rate.

Compliance with ethical standards

Funding

None reported.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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