Molecular and immunophenotypic biomarkers in dermato-oncology: insights from cutaneous melanoma and Sézary syndrome

The identification of reliable biomarkers represents a cornerstone of modern oncology, supporting early diagnosis, risk stratification, and treatment monitoring. Skin cancers constitute a particularly relevant field for biomarker research, encompassing both common malignancies such as cutaneous melanoma and rare but aggressive diseases like Sézary syndrome. Despite important therapeutic advances, significant challenges remain in both settings, highlighting the need for robust biomarkers capable of improving disease detection and guiding patient management. The first part of this thesis investigates the clinical value of circulating tumor DNA (ctDNA) as a minimally invasive biomarker in patients with resected stage III cutaneous melanoma receiving adjuvant therapy. In a prospective cohort of 32 patients with BRAF-mutated melanoma treated with BRAF/MEK inhibitors or anti-PD1 immunotherapy, ctDNA was quantified by droplet digital PCR targeting BRAFV600 mutations in plasma samples collected after surgery and at predefined time points during treatment. Baseline ctDNA detection identified patients at significantly higher risk of relapse and reduced overall survival. In addition, longitudinal ctDNA monitoring reflected disease dynamics during therapy, as patients who remained relapse-free cleared ctDNA from plasma, whereas persistent ctDNA detection anticipated disease recurrence. These findings support the potential integration of ctDNA analysis into risk stratification and follow-up strategies for stage III melanoma patients undergoing adjuvant treatment. The second part of the thesis focuses on the identification of immunophenotypic biomarkers in Sézary syndrome, an aggressive cutaneous T-cell lymphoma characterized by erythroderma, lymphadenopathy, and circulating malignant CD4⁺ T cells. Using multiparametric flow cytometry, the expression of the ectoenzymes CD39, CD73, and CD38 was assessed on circulating CD4⁺ T-cell subsets from 33 SS patients and longitudinally monitored during mogamulizumab treatment. SS cells displayed aberrant overexpression of CD39 or CD73 together with reduced CD38 expression, defining a tumor-specific immunophenotypic signature. Genetic analysis further identified the ENTPD1 SNP rs10748643 as a contributor to CD39 dysregulation. During mogamulizumab therapy, responders exhibited a marked reduction of CD39⁺ tumor cells and a concomitant increase in CD38 expression consistent with immune reconstitution of non-malignant T cells, whereas blood relapse was characterized by the re-expansion of CD39⁺CD38⁻ tumor cells retaining their aberrant phenotype. Overall, this thesis highlights how complementary molecular and immunophenotypic biomarker approaches can improve disease characterization and monitoring in both common and rare skin cancers. The integration of minimally invasive and immune-based biomarkers may contribute to more precise patient stratification and support personalized management strategies in dermato-oncology