Reflectance confocal microscopy for melanoma: systematic review with evidence-based recommendations

Dermoscopy has limited specificity for equivocal melanocytic lesions, causing unnecessary excisions. Reflectance confocal microscopy offers noninvasive, near-histological imaging, but evidence remains scattered. This review graded evidence across six melanoma applications (diagnosis, excision reduction, margin mapping, treatment monitoring, cost-effectiveness, and teledermatology) and derived recommendations. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PROSPERO CRD420261329819), PubMed, Web of Science, and Embase were searched (January 2005 to March 2026). Two reviewers independently performed study selection, data extraction, and risk-of-bias assessment (QUADAS-2, AMSTAR-2, CHEC). Evidence was graded (National Health and Medical Research Council) and synthesized narratively. Seventy primary studies and 13 systematic reviews were included. As a second-level test after dermoscopy, confocal microscopy preserved sensitivity (pooled 92-94%) and improved specificity (82 vs. 42% at 90% sensitivity). In the only diagnostic randomized trial, the number needed to excise fell 43%; real-world cohorts spared 23-61% of biopsies. For lentigo maligna, confocal microscopy was more sensitive and specific than dermoscopy and outperformed clinical and dermoscopic assessment for treatment failure; presurgical mapping reduced surgical stages (1.7 vs. 1.1). Two economic evaluations reported 27-49% lower costs per melanoma. Evidence was weaker for amelanotic, nodular, and acral melanoma, scoring systems, and teledermatology; risk of bias was often high or unclear. Four of 13 recommendations reached grade B, eight grade C, and one grade D. Evidence supports confocal microscopy as a second-level tool in specialist practice for dermoscopically equivocal melanocytic lesions, facial lentigo maligna diagnosis, reducing unnecessary excisions, and presurgical margin mapping. Multicentre randomized trials should precede broader adoption.