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

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.

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.

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.

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.

The major unresolved issues are optimal sequencing, response-adapted perioperative treatment, resistance, biomarker validation and treatment of transplant, frail and other under-represented populations.