In vivo reflectance confocal microscopy (RCM) enables monitoring of non-melanocytic skin cancers (NMSC) treated with non-invasive or minimally invasive therapies. This systematic review analyzed studies on NMSC treated with these therapies and monitored by RCM. A total of 56 articles were included, with 40 focusing on squamous conditions, such as actinic keratosis and squamous cell carcinoma, 15 on basal cell carcinoma (BCC), and 1 on extramammary Paget’s disease. Evaluated therapies included ablative laser, cryosurgery, photodynamic therapy, 5-fluorouracil, imiquimod, and tirbanibulin, among others. RCM demonstrated complete response in squamous conditions with normalization of the honeycomb pattern and reduction of scaling and parakeratosis, frequently allowing for detection of subclinical malignancy. In BCC, RCM showed complete response as disappearance of tumor islands. RCM allows treatment optimization and early monitoring, even when inflammation hinders clinical assessment. It is recommended that RCM evaluations be performed starting at least 1 month after treatment for squamous conditions and 3 months for BCC.
