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Meta-Analysis
. 2018 Dec 4;12(12):CD013190.
doi: 10.1002/14651858.CD013190.

Reflectance confocal microscopy for diagnosing cutaneous melanoma in adults

Jacqueline Dinnes  1 , Jonathan J Deeks, Daniel Saleh, Naomi Chuchu, Susan E Bayliss, Lopa Patel, Clare Davenport, Yemisi Takwoingi, Kathie Godfrey, Rubeta N Matin, Rakesh Patalay, Hywel C Williams; Cochrane Skin Cancer Diagnostic Test Accuracy Group
Affiliations
Meta-Analysis

Reflectance confocal microscopy for diagnosing cutaneous melanoma in adults

Jacqueline Dinnes et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

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Conflict of interest statement

JD: nothing to declare. JJD: nothing to declare. DS: nothing to declare. NC: nothing to declare. SEB: nothing to declare. LP: nothing to declare. CD: nothing to declare. YT: nothing to declare. KG: nothing to declare. RNM: "my institution received a grant for a Barco NV commercially sponsored study to evaluate digital dermoscopy in the skin cancer clinic. My institution also received Oxfordshire Health Services Research Charitable Funds for carrying out a study of feasibility of using the Skin Cancer Quality of Life Impact Tool (SCQOLIT) in non melanoma skin cancer. I have received royalties for the Oxford Handbook of Medical Dermatology (Oxford University Press). I have received payment from Public Health England for the "Be Clear on Cancer" skin cancer report. I have no conflicts of interest to declare that directly relate to the publication of this work." RP: nothing to declare. HCW: I am director of the NIHR Health Technology Assessment (HTA) Programme. HTA is part of the NIHR, which also supports the NIHR systematic reviews programme from which this work is funded.

Figures

1
1
Sample photographs of superficial spreading melanoma (left) and nodular melanoma (right). Copyright © 2010 Dr Rubeta Matin: reproduced with permission.
2
2
Reflectance confocal microscopy images of normal skin (top) and of lentigo maligna (bottom). Copyright © 2017 Dr Rakesh Patalay: reproduced with permission.
3
3
Caliber ID Vivascope 1500 with 3000 attachment. Copyright © 2017 Guy's & St Thomas' NHS Foundation Trust: reproduced with permission.
4
4
Current clinical pathway for people with skin lesions.
5
5
PRISMA flow diagram. RCM: reflectance confocal microscopy.
6
6
Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies.
7
7
Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study.
8
8
Forest plot of tests: reflectance confocal microscopy (RCM) and dermoscopy data in any lesion suspicious for melanoma for detection of invasive melanoma (malignant melanoma (MM)) and atypical intraepidermal melanocytic variants (or melanoma in situ (MiS)). FN: false negative; FP: false positive; TN: true negative; TP: true positive.
9
9
Summary receiver operating characteristic (ROC) comparing reflectance confocal microscopy (RCM) and dermoscopy in all lesions suspected of melanoma for detection of invasive melanoma or atypical intraepidermal melanocytic variants (malignant melanoma (MM) + melanoma in situ (MiS)).
10
10
Summary receiver operating characteristic (ROC) of paired comparisons of reflectance confocal microscopy (RCM) and dermoscopy in all lesions suspected of melanoma for detection of invasive melanoma or atypical intraepidermal melanocytic variants (malignant melanoma (MM) + melanoma in situ (MiS)).
11
11
Forest plot of tests: reflectance confocal microscopy (RCM) and dermoscopy in equivocal lesion populations for detection of invasive melanoma (malignant melanoma (MM)) and atypical intraepidermal melanocytic variants (melanoma in situ (MiS). FN: false negative; FP: false positive; TN: true negative; TP: true positive.
12
12
Summary receiver operating characteristic (ROC) comparing reflectance confocal microscopy (RCM) and dermoscopy in equivocal lesion populations for detection of invasive melanoma (malignant melanoma (MM)) and atypical intraepidermal melanocytic variants (or melanoma in situ (MiS)).
13
13
Summary receiver operating characteristic (ROC) for paired comparisons of reflectance confocal microscopy (RCM) and dermoscopy in equivocal lesion populations for detection of invasive melanoma (malignant melanoma (MM)) and atypical intraepidermal melanocytic variants (or melanoma in situ (MiS)).
14
14
Forest plot: reflectance confocal microscopy (RCM) results by algorithm, threshold, and number of observers for diagnosis of invasive melanoma (malignant melanoma (MM)) and atypical intraepidermal melanocytic variants (or melanoma in situ (MiS)). FN: false negative; FP: false positive; TN: true negative; TP: true positive.
15
15
Summary receiver operating characteristic plot comparing studies which used and did not use an algorithm or scale to assist reflectance confocal microscopy (RCM) diagnosis (0 = none, 1 = tool used): outcome was detection of invasive melanoma (malignant melanoma (MM)) and atypical intraepidermal melanocytic variants (or melanoma in situ (MiS)).
16
16
Summary receiver operating characteristic (ROC) plot: comparison of in‐person and Image based studies of reflectance confocal microscopy (RCM) for detection of invasive melanoma (malignant melanoma (MM)) and atypical intraepidermal melanocytic variants (or melanoma in situ (MiS)).
17
17
Summary receiver operating characteristic (ROC) plot comparing reflectance confocal microscopy (RCM) performance in studies of all lesions suspected of melanoma with those in participants with equivocal lesions (for detection of invasive melanoma (malignant melanoma (MM)) and atypical intraepidermal melanocytic variants (or melanoma in situ (MiS))).
18
18
Forest plot: reflectance confocal microscopy (RCM) diagnosis in studies of participants with equivocal lesions by observer experience, for the detection of invasive melanoma (malignant melanoma (MM)), of invasive melanoma and atypical intraepidermal melanocytic variants (or melanoma in situ (MiS)) (MM+MiS), and of any potential skin cancer (melanoma or other skin cancer) or skin lesion with a high risk of progression to melanoma (any). FN: false negative; FP: false positive; TN: true negative; TP: true positive.
19
19
Forest plot: reflectance confocal microscopy (RCM) diagnosis in studies of all lesions suspected of melanoma by observer experience, for the detection of invasive melanoma (malignant melanoma (MM)), of invasive melanoma and atypical intraepidermal melanocytic variants (or melanoma in situ (MiS)) (MM+MiS), and of any potential skin cancer (melanoma or other skin cancer) or skin lesion with a high risk of progression to melanoma (any). FN: false negative; FP: false positive; TN: true negative; TP: true positive.
20
20
Forest plot of reflectance confocal microscopy (RCM) performance by study group and target condition definition (invasive melanoma alone (malignant melanoma (MM)), invasive melanoma and atypical intraepidermal melanocytic variants, or melanoma in situ (MiS) (MM+MiS), and for any skin cancer or skin lesion with a high risk of progression to melanoma (any)). FN: false negative; FP: false positive; TN: true negative; TP: true positive.
21
21
Forest plot: reflectance confocal microscopy (RCM) results by algorithm and threshold for diagnosis of invasive melanoma (MM). FN: false negative; FP: false positive; TN: true negative; TP: true positive.
22
22
Forest plot: reflectance confocal microscopy (RCM) results by algorithm and threshold for diagnosis of any skin cancer or skin lesion with a high risk of progression to melanoma (any). FN: false negative; FP: false positive; TN: true negative; TP: true positive.
1
1. Test
Reflectance confocal microscopy (RCM) in any lesion suspicious for melanoma (malignant melanoma (MM)).
2
2. Test
RCM in studies of other lesion types (MM).
3
3. Test
RCM in any lesion suspicious for melanoma (malignant melanoma + melanoma in situ (MM+MiS)).
4
4. Test
RCM in equivocal lesion studies (MM+MiS).
5
5. Test
RCM in studies of other lesion types (MM+MiS).
6
6. Test
Dermoscopy in any lesion suspicious for melanoma (MM+MiS).
7
7. Test
Dermoscopy in equivocal lesion studies (MM+MiS).
8
8. Test
Dermoscopy in studies of other lesion types (MM+MiS).
9
9. Test
RCM in any lesion suspicious for melanoma (any).
10
10. Test
RCM in equivocal lesion studies (any).
11
11. Test
RCM score at ≥ 3 (MM).
12
12. Test
Segura algorithm at > ‐1 (MM).
13
13. Test
Guitera 2 step algorithm (significant characteristics) (MM).
14
14. Test
No algorithm (observer diagnosis) (MM).
15
15. Test
No algorithm (significant characteristics) (MM).
16
16. Test
RCM score at ≥ 2 (MM+MiS).
17
17. Test
RCM score at ≥ 3 (MM+MiS).
18
18. Test
RCM score at threshold NR (likely ≥ 3) (MM+MiS).
19
19. Test
RCM score at ≥ 4 (MM+MiS).
20
20. Test
Segura algorithm at > ‐1 (MM+MiS).
21
21. Test
Guitera 2 step algorithm (significant chars for MM) (MM+MiS).
22
22. Test
Pellacani 2 step algorithm (dysplastic MM) image based (MM+MiS).
23
23. Test
RCM computer assisted diagnosis algorithm (MM+MiS).
24
24. Test
No algorithm (significant characteristics) (MM+MiS).
25
25. Test
No algorithm (selected characteristics) (MM+MiS).
26
26. Test
No algorithm (observer diagnosis) (MM+MiS).
27
27. Test
No algorithm (observer diagnosis) paired in‐person (MM+MiS).
28
28. Test
No algorithm (excise decision) (MM+MiS).
29
29. Test
No algorithm (excise decision) paired in‐person (MM+MiS).
30
30. Test
RCM score at ≥ 3 (any).
31
31. Test
RCM score at threshold not reported (likely ≥ 3) (any).
32
32. Test
Segura algorithm at > ‐1 (any).
33
33. Test
Pellacani 2 step algorithm (dysplastic‐MM) (any).
34
34. Test
Guitera 2 step algorithm (significant characteristics) (any).
35
35. Test
No algorithm (observer diagnosis) (any).
36
36. Test
No algorithm (observer diagnosis) paired in‐person (any).
37
37. Test
No algorithm (excise decision) (any).
38
38. Test
No algorithm (excise decision) paired in‐person (any).
39
39. Test
Observer experience high ‐ any lesion suspicious for melanoma (MM).
40
40. Test
Observer experience low ‐ any lesion suspicious for melanoma (MM).
41
41. Test
MM1 observer experience high other.
42
42. Test
MM1 observer experience not reported other.
43
43. Test
Observer experience high ‐ any lesion suspicious for melanoma (MM+MiS).
44
44. Test
Observer experience low ‐ any lesion suspicious for melanoma (MM+MiS).
45
45. Test
Observer experience high ‐ equivocal lesion studies (MM+MiS).
46
46. Test
Observer experience low ‐ equivocal lesion studies (MM+MiS).
47
47. Test
Observer experience not reported ‐ equivocal lesion studies (MM+MiS).
48
48. Test
Observer experience not reported ‐ other study populations (MM+MiS).
49
49. Test
Observer experience high ‐ equivocal lesion studies (any).
50
50. Test
Observer experience low ‐ equivocal lesion studies (any).
51
51. Test
Observer experience high ‐ any lesion suspicious for melanoma (any).
52
52. Test
Observer experience low ‐ any lesion suspicious for melanoma (any).
53
53. Test
MM2 any scale.
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de Carvalho 2016 {published data only}
    1. Carvalho N, Guida S, Abraham LS, Cesinaro AM, Farnetani F, Bonamonte D, et al. Pink melanocytic and non‐melanocytic lesions: how reflectance confocal microscopy can help in differential diagnosis. Journal of the European Academy of Dermatology and Venereology : JEADV 2016;30(6):1026‐9. [PUBMED: 25753043] - PubMed
Edwards 2016 {published data only}
    1. Edwards SJ, Mavranezouli I, Osei‐Assibey G, Marceniuk G, Wakefield V, Karner C. VivaScope 1500 and 3000 systems for detecting and monitoring skin lesions: a systematic review and economic evaluation. Health Technology Assessment (Winchester, England) 2016;20(58):1‐260. [PUBMED: 27483991] - PMC - PubMed
Eichert 2010 {published data only}
    1. Eichert S, Mohrle M, Breuninger H, Rocken M, Garbe C, Bauer J. Diagnosis of cutaneous tumors with in vivo confocal laser scanning microscopy. Journal der Deutschen Dermatologischen Gesellschaft 2010;8(6):400‐10. - PubMed
Gareau 2009 {published data only}
    1. Gareau DS, Karen JK, Dusza SW, Tudisco M, Nehal KS, Rajadhyaksha M. Sensitivity and specificity for detecting basal cell carcinomas in Mohs excisions with confocal fluorescence mosaicing microscopy. Journal of Biomedical Optics 2009;14(3):034012. [PUBMED: 19566305] - PMC - PubMed
Gerger 2005 {published data only}
    1. Gerger A, Koller S, Kern T, Massone C, Steiger K, Richtig E, et al. Diagnostic applicability of in vivo confocal laser scanning microscopy in melanocytic skin tumors. Journal of Investigative Dermatology 2005;124(3):493‐8. [PUBMED: 15737188] - PubMed
Gerger 2006 {published data only}
    1. Gerger A, Kerl H, Samonigg H, Langsenlehner U, Krippl P, Smolle J. Sensitivity and specificity of confocal laser scanning microscopy for in vivo diagnosis of malignant skin tumors. Journal of Investigative Dermatology 2006;126(Suppl 3):s114. - PubMed
Gerger 2008a {published data only}
    1. Gerger A, Wiltgen M, Langsenlehner U, Richtig E, Horn M, Weger W, et al. Diagnostic image analysis of malignant melanoma in in vivo confocal laser‐scanning microscopy: a preliminary study. Skin Research & Technology 2008;14(3):359‐63. [PUBMED: 19159384] - PubMed
Gerger 2008b {published data only}
    1. Gerger A, Hofmann‐Wellenhof R, Langsenlehner U, Richtig E, Koller S, Weger W, et al. In vivo confocal laser scanning microscopy of melanocytic skin tumours: diagnostic applicability using unselected tumour images. British Journal of Dermatology 2008;158(2):329‐33. - PubMed
Giambrone 2015 {published data only}
    1. Giambrone D, Alamgir M, Masud A, Bronsnick T, Rao B. The diagnostic accuracy of in vivo confocal microscopy in clinical practice. Journal of the American Academy of Dermatology 2015;73(2):317‐9. [PUBMED: 26183976] - PubMed
Gill 2014 {published data only}
    1. Gill M, Longo C, Farnetani F, Cesinaro AM, Gonzalez S, Pellacani G. Non‐invasive in vivo dermatopathology: identification of reflectance confocal microscopic correlates to specific histological features seen in melanocytic neoplasms. Journal of the European Academy of Dermatology and Venereology : JEADV 2014;28(8):1069‐78. [PUBMED: 24147614] - PubMed
Gonzalez 2002 {published data only}
    1. Gonzalez S, Tannous Z. Real‐time in vivo confocal reflectance microscopy of basal cell carcinoma. Journal of the American Academy of Dermatology 2002;47(6):869‐74. [PUBMED: 12451371] - PubMed
Gonzalez 2013 {published data only}
    1. Gonzalez S. Should reflectance confocal microscopy be the gold standard for basal cell carcinoma diagnosis?. Imaging in Medicine 2013;5(4):299‐301. [DOI: 10.2217/IIM.13.36] - DOI
Guida 2015 {published data only}
    1. Guida S, Longo C, Casari A, Ciardo S, Manfredini M, Reggiani C, et al. Update on the use of confocal microscopy in melanoma and non‐melanoma skin cancer. Giornale Italiano di Dermatologia e Venereologia 2015;150(5):547‐63. [PUBMED: 26140397] - PubMed
Guitera 2010 {published data only}
    1. Guitera P, Pellacani G, Crotty KA, Scolyer RA, Li LX, Bassoli S, et al. The impact of in vivo reflectance confocal microscopy on the diagnostic accuracy of lentigo maligna and equivocal pigmented and nonpigmented macules of the face. Journal of Investigative Dermatology 2010;130(8):2080‐91. [PUBMED: 20393481] - PubMed
Guitera 2013 {published data only}
    1. Guitera P, Moloney FJ, Menzies SW, Stretch JR, Quinn MJ, Hong A, et al. Improving management and patient care in lentigo maligna by mapping with in vivo confocal microscopy. JAMA Dermatology 2013;149(6):692‐8. [PUBMED: 23553208] - PubMed
Haenssle 2006 {published data only}
    1. Haenssle HA, Krueger U, Vente C, Thoms KM, Bertsch HP, Zutt M, et al. Results from an observational trial: digital epiluminescence microscopy follow‐up of atypical nevi increases the sensitivity and the chance of success of conventional dermoscopy in detecting melanoma. Journal of Investigative Dermatology 2006;126(5):980‐5. [PUBMED: 16514414] - PubMed
Hennessy 2010 {published data only}
    1. Hennessy R, Jacques S, Pellacani G, Gareau D. Clinical feasibility of rapid confocal melanoma feature detection. Proceedings of SPIE. 2 March 2010; Vol. 7548. [DOI: 10.1117/12.842824] - DOI
Hoogedoorn 2014 {published data only}
    1. Hoogedoorn L, Peppelman M, Erp PEJ, Gerritsen MJP. The use of in vivo reflectance confocal microscopy in clinical practice: prospective differentiation of difficult to distinguish nodular basal cell carcinomas and intradermal nevi. Nederlands Tijdschrift voor Dermatologie en Venereologie 2014;24(1):48. [EMBASE: 71623025]
Hoogedoorn 2015 {published data only}
    1. Hoogedoorn L, Peppelman M, Blokx WA, Erp PE, Gerritsen MJ. Prospective differentiation of clinically difficult to distinguish nodular basal cell carcinomas and intradermal nevi by non‐invasive reflectance confocal microscopy: a case series study. Journal of the European Academy of Dermatology and Venereology : JEADV 2015;29(2):330‐6. [PUBMED: 24841762] - PubMed
Humphrey 2006 {published data only}
    1. Humphrey S, Walsh NM, Delaney L, Propperova I, Langley RG. Prognostic significance of vascularity in cutaneous melanoma: pilot study using in vivo confocal scanning laser microscopy. Journal of Cutaneous Medicine and Surgery 2006;10(3):122‐7. [PUBMED: 17241587] - PubMed
Incel 2015 {published data only}
    1. Incel P, Gurel MS, Erdemir AV. Vascular patterns of nonpigmented tumoral skin lesions: confocal perspectives. Skin Research and Technology 2015;21(3):333‐9. - PubMed
Kadouch 2015a {published data only}
    1. Kadouch DJ, Schram ME, Leeflang MM, Limpens J, Spuls PI, Rie MA. In vivo confocal microscopy of basal cell carcinoma: a systematic review of diagnostic accuracy. Journal of the European Academy of Dermatology and Venereology : JEADV 2015;29(10):1890‐7. [PUBMED: 26290493] - PubMed
Kadouch 2015b {published data only}
    1. Kadouch DJ, Wolkerstorfer A, Elshot Y, Zupan‐Kajcovski B, Crijns MB, Starink MV, et al. Treatment of basal cell carcinoma using a one‐stop‐shop with reflectance confocal microscopy: study design and protocol of a randomized controlled multicenter trial. JMIR Research Protocols 2015;4(3):e109. [PUBMED: 26362616] - PMC - PubMed
Kose 2014 {published data only}
    1. Kose K, Cordova M, Duffy M, Flores ES, Brooks DH, Rajadhyaksha M. Video‐mosaicing of reflectance confocal images for examination of extended areas of skin in vivo. British Journal of Dermatology 2014;171(5):1239‐41. [PUBMED: 24720744] - PMC - PubMed
Langley 2001 {published data only}
    1. Langley RG, Rajadhyaksha M, Dwyer PJ, Sober AJ, Flotte TJ, Anderson RR. Confocal scanning laser microscopy of benign and malignant melanocytic skin lesions in vivo. Journal of the American Academy of Dermatology 2001;45(3):365‐76. [PUBMED: 11511832] - PubMed
Langley 2006 {published data only}
    1. Langley RG, Burton E, Walsh N, Propperova I, Murray SJ. In vivo confocal scanning laser microscopy of benign lentigines: comparison to conventional histology and in vivo characteristics of lentigo maligna. Journal of the American Academy of Dermatology 2006;55(1):88‐97. [PUBMED: 16781299] - PubMed
Losi 2014 {published data only}
    1. Losi A, Longo C, Cesinaro AM, Benati E, Witkowski A, Guitera P, et al. Hyporeflective pagetoid cells: a new clue for amelanotic melanoma diagnosis by reflectance confocal microscopy. British Journal of Dermatology 2014;171(1):48‐54. [PUBMED: 24329036] - PubMed
Maier 2013 {published data only}
    1. Maier T, Sattler EC, Braun‐Falco M, Korting HC, Ruzicka T, Berking C. Reflectance confocal microscopy in the diagnosis of partially and completely amelanotic melanoma: report on seven cases. Journal of the European Academy of Dermatology and Venereology : JEADV 2013;27(1):e42‐52. [PUBMED: 22324783] - PubMed
Malvehy 2012 {published data only}
    1. Malvehy J, Hanke‐Martinez M, Costa J, Salerni G, Carrera C, Puig S. Semiology and pattern analysis in nonmelanocytic lesions. Reflectance Confocal Microscopy for Skin Diseases. Berlin, Heidelberg: Springer, 2012:239‐52. [DOI: 10.1007/978-3-642-21997-9_18] - DOI
Menge 2016 {published data only}
    1. Menge TD, Hibler BP, Cordova MA, Nehal KS, Rossi AM. Concordance of handheld reflectance confocal microscopy (RCM) with histopathology in the diagnosis of lentigo maligna (LM): a prospective study. Journal of the American Academy of Dermatology 2016;74(6):1114‐20. [PUBMED: 26826051] - PubMed
Miller 2011 {published data only}
    1. Miller JH, Chrisler WB, Wang X, Sowa MB. Confocal microscopy for modeling electron microbeam irradiation of skin. Radiation and Environmental Biophysics 2011;50(3):365‐9. [PUBMED: 21604000] - PubMed
Nobre 2011 {published data only}
    1. Nobre Moura F, Dalle S, Depaepe L, Durupt F, Balme B, Thomas L. Melanoma: early diagnosis using in vivo reflectance confocal microscopy. Clinical and Experimental Dermatology 2011;36(2):209‐11. [PUBMED: 20659120] - PubMed
Nori 2004 {published data only}
    1. Nori S, Rius‐Diaz F, Cuevas J, Goldgeier M, Jaen P, Torres Abel, et al. Sensitivity and specificity of reflectance‐mode confocal microscopy for in vivo diagnosis of basal cell carcinoma: a multicenter study. Journal of the American Academy of Dermatology 2004;51(6):923‐30. [ER4:15466027; PUBMED: 15583584] - PubMed
Pellacani 2005 {published data only}
    1. Pellacani G, Cesinaro AM, Seidenari S. Reflectance‐mode confocal microscopy of pigmented skin lesions ‐ improvement in melanoma diagnostic specificity. Journal of the American Academy of Dermatology 2005;53(6):979‐85. [PUBMED: 16310058] - PubMed
Pellacani 2007b {published data only}
    1. Pellacani G, Bassoli S, Longo C, Cesinaro AM, Seidenari S. Diving into the blue: in vivo microscopic characterization of the dermoscopic blue hue. Journal of the American Academy of Dermatology 2007;57(1):96‐104. [PUBMED: 17485141] - PubMed
Pellacani 2008 {published data only}
    1. Pellacani G, Longo C, Malvehy J, Puig S, Carrera C, Segura S, et al. In vivo confocal microscopic and histopathologic correlations of dermoscopic features in 202 melanocytic lesions. Archives of Dermatology 2008;144(12):1597‐608. [PUBMED: 19075142] - PubMed
Pellacani 2009a {published data only}
    1. Pellacani G, Vinceti M, Bassoli S, Braun R, Gonzalez S, Guitera P, et al. Reflectance confocal microscopy and features of melanocytic lesions: an internet‐based study of the reproducibility of terminology. Archives of Dermatology 2009;145(10):1137‐43. [PUBMED: 19841401] - PubMed
Peppelman 2013 {published data only}
    1. Peppelman M, Wolberink EA, Blokx WA, Kerkhof PC, Erp PE, Gerritsen MJ. In vivo diagnosis of basal cell carcinoma subtype by reflectance confocal microscopy. Dermatology 2013;227(3):255‐62. [PUBMED: 24158236] - PubMed
Peppelman 2015 {published data only}
    1. Peppelman M, Nguyen KP, Hoogedoorn L, Erp PE, Gerritsen MJ. Reflectance confocal microscopy: non‐invasive distinction between actinic keratosis and squamous cell carcinoma. Journal of the European Academy of Dermatology and Venereology 2015;29(7):1302‐9. [PUBMED: 25357235] - PubMed
Peppelman 2016 {published data only}
    1. Peppelman M, Nguyen KP, Alkemade HA, Maessen‐Visch B, Hendriks JC, Erp PE, et al. Diagnosis of basal cell carcinoma by reflectance confocal microscopy: study design and protocol of a randomized controlled multicenter trial. JMIR Research Protocols 2016;5(2):e114. [PUBMED: 27363577] - PMC - PubMed
Puig 2012 {published data only}
    1. Puig S, Giacomo TB, Serra D, Cabrini F, Alos L, Palou J, et al. Reflectance confocal microscopy of blue nevus. European Journal of Dermatology 2012;22(4):552‐3. [PUBMED: 22735078] - PubMed
Reggiani 2015 {published data only}
    1. Reggiani C, Manfredini M, Mandel VD, Farnetani F, Ciardo S, Bassoli S, et al. Update on non‐invasive imaging techniques in early diagnosis of non‐melanoma skin cancer. Giornale Italiano di Dermatologia e Venereologia 2015;150(4):393‐405. [PUBMED: 26184797] - PubMed
Rishpon 2009 {published data only}
    1. Rishpon A, Kim N, Scope A, Porges L, Oliviero MC, Braun RP, et al. Reflectance confocal microscopy criteria for squamous cell carcinomas and actinic keratoses. Archives of Dermatology 2009;145(7):766‐72. [PUBMED: 19620557] - PubMed
Röwert‐Huber 2007 {published data only}
    1. Röwert‐Huber J, Patel MJ, Forschner T, Ulrich C, Eberle J, Kerl H, et al. Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification. British Journal of Dermatology 2007;156(Suppl 3):8‐12. [PUBMED: 17488400] - PubMed
Salerni 2011 {published data only}
    1. Salerni G, Lovatto L, Carrera C, Palou J, Alos L, Puig‐Butille JA, et al. Correlation among dermoscopy, confocal reflectance microscopy, and histologic features of melanoma and basal cell carcinoma collision tumor. Dermatologic Surgery 2011;37(2):275‐9. [PUBMED: 21281387] - PubMed
Scope 2009 {published data only}
    1. Scope A, Mecca PS, Marghoob AA. skINsight lessons in reflectance confocal microscopy: rapid diagnosis of pigmented basal cell carcinoma. Archives of Dermatology 2009;145(1):106‐7. [PUBMED: 19153366] - PubMed
Scope 2014 {published data only}
    1. Scope A, Longo C. Recognizing the benefits and pitfalls of reflectance confocal microscopy in melanoma diagnosis. Dermatology Practical & Conceptual 2014;4(3):67‐71. [DOI: 10.5826/dpc.0403a13] - DOI - PMC - PubMed
Soyer 2013 {published data only}
    1. Soyer HP, Prow TW. Reflectance confocal microscopy in the diagnosis of nodular skin lesions. British Journal of Dermatology 2013;169(1):4. [PUBMED: 23834114] - PubMed
Steiner 1992 {published data only}
    1. Steiner A, Pehamberger H, Binder M, Wolff K. Pigmented Spitz nevi: improvement of the diagnostic accuracy by epiluminescence microscopy. Journal of the American Academy of Dermatology 1992;27(5 Pt 1):697‐701. [PUBMED: 1430390] - PubMed
Stephens 2013 {published data only}
    1. Stephens A, Fraga‐Braghiroli N, Oliviero M, Rabinovitz H, Scope A. Spoke wheel‐like structures in superficial basal cell carcinoma: a correlation between dermoscopy, histopathology, and reflective confocal microscopy. Journal of the American Academy of Dermatology 2013;69(5):e219‐21. [PUBMED: 24124839] - PubMed
Stevenson 2013 {published data only}
    1. Stevenson AD, Mickan S, Mallett S, Ayya M. Systematic review of diagnostic accuracy of reflectance confocal microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions. Dermatology Practical & Conceptual 2013;3(4):19‐27. [DOI: 10.5826/dpc.0304a05] - DOI - PMC - PubMed
Tannous 2009 {published data only}
    1. Tannous Z, Al‐Arashi M, Shah S, Yaroslavsky AN. Delineating melanoma using multimodal polarized light imaging. Lasers in Surgery and Medicine 2009;41(1):10‐6. [PUBMED: 19143015] - PubMed
Willard 2011 {published data only}
    1. Willard K, Warschaw KE, Swanson DL. Use of reflectance confocal microscopy to differentiate hidrocystoma from basal cell carcinoma. Dermatologic Surgery 2011;37(3):392‐4. [PUBMED: 21314800] - PubMed
Witkowski 2016 {published data only}
    1. Witkowski AM, Ludzik J, DeCarvalho N, Ciardo S, Longo C, DiNardo A, et al. Non‐invasive diagnosis of pink basal cell carcinoma: how much can we rely on dermoscopy and reflectance confocal microscopy?. Skin Research and Technology 2016;22(2):230‐7. [ER4:25012281; PUBMED: 26338448] - PubMed
Xiong 2016 {published data only}
    1. Xiong YD, Ma S, Li X, Zhong X, Duan C, Chen Q. A meta‐analysis of reflectance confocal microscopy for the diagnosis of malignant skin tumours. Journal of the European Academy of Dermatology and Venereology : JEADV 2016;30(8):1295‐302. [PUBMED: 27230832] - PubMed
Yelamos 2016 {published data only}
    1. Yelamos O, Nehal KS. Integrating clinical information, dermoscopy and reflectance confocal microscopy to improve the diagnostic accuracy and confidence of amelanotic and lightly pigmented melanomas. British Journal of Dermatology 2016;175(6):1147‐8. [PUBMED: 27996145] - PubMed

References to studies awaiting assessment

Borsari 2016 {published data only}
    1. Borsari S, Pampena R, Lallas A, Kyrgidis A, Moscarella E, Benati E, et al. Clinical indications for use of reflectance confocal microscopy for skin cancer diagnosis. JAMA Dermatology 2016;152(10):1093‐8. [PUBMED: 27580185] - PubMed
Guitera 2016 {published data only}
    1. Guitera P, Menzies SW, Argenziano G, Longo C, Losi A, Drummond M, et al. Dermoscopy and in vivo confocal microscopy are complementary techniques for diagnosis of difficult amelanotic and light‐coloured skin lesions. British Journal of Dermatology 2016;175(6):1311‐9. [PUBMED: 27177158 ] - PubMed
Jain 2017 {published data only}
    1. Jain M, Pulijal SV, Rajadhyaksha M. The bedside diagnostic accuracy of a novice reflectance confocal microscopy reader for skin cancer detection in vivo in real‐time: understanding challenges and potential pitfalls. Proceedings of SPIE. 24 March 2017; Vol. 10060. [DOI: 10.1117/12.2255685] - DOI
Ludzik 2016 {published data only}
    1. Ludzik J, Witkowski AM, Roterman‐Konieczna I, Bassoli S, Farnetani F, Pellacani G. Improving diagnostic accuracy of dermoscopically equivocal pink cutaneous lesions with reflectance confocal microscopy in telemedicine settings: double reader concordance evaluation of 316 cases. PloS One 2016;11(9):e0162495. [PUBMED: 27606812] - PMC - PubMed

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