Contemporary Multimodal Management of Cutaneous Malignancies: Surgery, Radiotherapy, Systemic Therapy, Molecular Targeting and Immunotherapy.

BACKGROUND: The therapeutic management of cutaneous malignancies-cutaneous melanoma, cutaneous squamous-cell carcinoma (cSCC), basal-cell carcinoma (BCC) and Merkel-cell carcinoma (MCC)-has shifted toward multimodal, stage-adapted treatment integrating surgery, radiotherapy, molecularly targeted therapy and immune checkpoint inhibition. METHODS: We conducted a structured narrative review with a structured literature search of PubMed/MEDLINE, Scopus and Web of Science (January 2015-6 September 2026), prioritising current clinical practice guidelines, randomised controlled trials and phase II-III studies; landmark older trials were included separately. SYNTHESIS: Surgery with adequate histological margins, including Mohs micrographic surgery where appropriate, remains definitive for localised disease. In resectable macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab with response-driven postoperative management improved event-free survival versus adjuvant nivolumab in NADINA. SWOG S1801 independently demonstrated an event-free-survival advantage for perioperative pembrolizumab over adjuvant-only pembrolizumab in resectable stage III-IV melanoma. In advanced melanoma, dual immune-checkpoint strategies and BRAF/MEK inhibition require patient-specific sequencing; in the European Union, nivolumab plus relatlimab is authorised for first-line advanced melanoma with tumour-cell PD-L1 expression <1%. In high-risk cSCC after surgery and radiotherapy, adjuvant cemiplimab improved disease-free survival. In advanced BCC, Hedgehog-pathway inhibitors remain the principal first systemic option, with anti-PD-1 therapy after HHI failure or intolerance. CLINICAL IMPLICATIONS: Molecular testing should be indication-driven: BRAF V600 is a validated treatment-selecting biomarker, while broader NGS profiling (including NRAS, KIT, NF1, TERT and co-occurring alterations), PD-L1, tumour mutational burden and circulating tumour DNA have context-dependent, supportive or investigational roles. CONCLUSIONS: The major unresolved issues are optimal sequencing, response-adapted perioperative treatment, resistance, biomarker validation and treatment of transplant, frail and other under-represented populations.