Yuliya Yakymiv, Sara Marchisio, Erika Ortolan, Cristiano Bracci, Rebecca Senetta, Maria Rebecca Rumore, Cristian Tampieri, Marianna Fia, Simone Ribero, Ada Funa

Cutaneous T-cell lymphoma (CTCL), characterized by malignant T-cell proliferation primarily in the skin, includes subtypes such as mycosis fungoides (MF) and Sézary syndrome (SS). The tumor microenvironment (TME) is central to their pathogenesis, with flow cytometry and histology being the gold standards for detecting malignant T cells within the TME. Alongside emerging molecular markers, particularly clonality analysis, these tools are indispensable for accurate diagnosis and treatment planning. Of note, adenosine signaling within the TME has been shown to suppress immune responses, affecting various cell types. The expression of CD39, CD73, and CD38, enzymes involved in adenosine production, can be elevated in MF and SS, contributing to immune suppression. Conversely, the expression of CD26, part of the adenosine deaminase/CD26 complex, that degrades adenosine, is often lost by circulating tumoral cells. Flow cytometry has demonstrated increased levels of CD39 and CD73 on Sézary cells, correlating with disease progression and prognosis, while CD38 shows a variable expression, with its prognostic significance remaining under investigation. Understanding these markers’ roles in the complexity of TME-mediated immune evasion mechanisms might enhance diagnostic precision and offer new therapeutic targets in CTCL.

The etiology of melanoma is multifactorial and arises from the interplay of genetic, phenotypic, and environmental factors. The genetic predisposition to melanoma is influenced by a complex interaction among genes exhibiting varying levels of penetrance (high, moderate, and low), each contributing differently to the susceptibility of the disease. Furthermore, penetrance may vary based on the incidence of melanoma across diverse populations and geographical regions. Advances in genetic sequencing technologies have facilitated the identification of novel genes potentially associated with melanoma, as well as the characterization of relevant germline variants. While the most extensively researched variant is CDKN2A, recent studies have highlighted other variants unrelated to CDKN2A as significant areas of investigation. Among them, high-penetrance genes encompass CDK4, BAP1, POT1, TERT, ACD, and TERF2IP. In contrast, moderate-penetrance genes include MC1R, MITF, and SLC45A2, while low-penetrance genes consist of OCA2, TYRP1, and TYR. In addition to elevating the risk of melanoma, these genetic alterations may also predispose individuals to internal neoplasms. This review aims to provide a comprehensive overview of the definitions of sporadic, multiple primary, familial, and hereditary melanoma, with a particular emphasis on non-CDKN2A germline variants and their dermoscopic and phenotypic features.

Summary: Sézary syndrome (SS) is an aggressive cutaneous T‐cell lymphoma, characterized by erythroderma, lymphadenopathy and circulating malignant CD4 ⁺ T cells. Despite therapeutic advances, SS remains an incurable disease. Early diagnosis is therefore essential for timely therapeutic intervention; however, reliable biomarkers to identify circulating SS cells are still lacking. Recent studies highlighted dysregulation of the ectoenzymes CD39, CD73 and CD38 in SS, suggesting a potential role for these molecules in the disease. Thirty‐three patients were enrolled in this study, and CD39/CD73/CD38 expression was analysed on circulating CD4 ⁺ T cells by multiparametric flow cytometry, enabling discrimination between malignant and non‐malignant T‐cell subsets. SS cells exhibited marked CD39 or CD73 overexpression together with consistent CD38 downregulation, a pattern also confirmed in paired skin biopsy, whereas non‐malignant CD4 ⁺ T cells largely maintained expression profiles comparable to healthy controls. Genotyping further identified ENTPD1 single nucleotide polymorphism rs10748643 as a contributor to CD39 dysregulation, defining a CD39‐permissive subgroup characterized by CD39 ⁺ SS cells. In conclusion, the combined overexpression of CD39 or CD73 and loss of CD38 defines a distinct tumour‐restricted immunophenotypic signature in SS. Integrating these ectoenzymes into flow cytometry panels may improve detection of malignant CD4 ⁺ T cells across blood and skin, eventually strengthening diagnostic accuracy.