Where Reflectance Confocal Microscopy Provides the Greatest Benefit for Diagnosing Skin Cancers: The Experience of the National Cancer Institute of Naples

<b>Background</b>: Although complete excision of suspicious melanocytic lesions is mandatory, it carries the risk of unnecessary scarring on one hand and inadequate treatment of misdiagnosed lesions on the other. <b>Objectives</b>: We evaluated the sensitivity, specificity, and predictive value of reflectance confocal microscopy (RCM) in diagnosing pigmented lesions with clinically ambiguous features-the so-called "gray zone" -and compared its performance with the more established technique of epiluminescence microscopy (ELM). <b>Results</b>: Between 2019 and 2020, a total of 2282 melanocytic lesions were assessed using both ELM and RCM. Histopathological diagnosis aligned with the ELM risk classification in 91.6% of melanocytic lesions, specifically in 92.0% of very-high-risk lesions, 88.5% of high-risk lesions, 66.3% of medium-risk lesions, 96.3% of low-risk lesions, and 98.0% of very low-risk lesions. Similarly, histopathological diagnosis of these lesions corresponded with the RCM risk assessment in 91.2% of cases, including 90.9% of very-high-risk lesions, 84.4% of high-risk lesions, 93.1% of medium-risk lesions, 90.5% of low-risk lesions, and 96.2% of very low-risk lesions. <b>Conclusions</b>: Although ELM is a valuable tool for increasing the efficacy of clinical diagnosis, its reliability decreases for a group of lesions that appear suspicious during clinical skin examination. RCM, as a newer technique, appears to improve malignancy detection in suspicious melanocytic lesions without requiring excision; its sensitivity and specificity remain high even in lesions classified by ELM as posing a medium risk of malignancy.