Genomic heterogeneity in primary cutaneous follicular center lymphomas reveals different clinicopathological subgroups.

Primary cutaneous follicle center lymphomas (PCFCLs) are indolent B-cell neoplasms limited to the skin and effectively managed with local therapies. Distinguishing PCFCL from systemic follicular lymphoma (sFL) with cutaneous involvement (FL_CI) is challenging due to overlapping features. We performed an integrated pathological and genetic analysis of skin samples of 24 PCFCL and 10 FL_CI, which showed subtle pathological changes (decreased BCL2 and CD10, increased CD23 expression in PCFCL), but markedly distinct mutational landscapes. FL_CI exhibited recurrent mutations in chromatin-modifying genes (CREBBP 90%, KMT2D 90%, and EP300 30%), closely resembling sFL. In contrast, PCFCL displayed a more heterogeneous profile, with mutations affecting B-cell development, cell adhesion, and immune evasion. These molecular alterations identified three distinct PCFCL subgroups. Group 1 (44%) harbored mutations in immune evasion genes (IRF8, FAS, CIITA, and B2M) and was associated with CD10 negativity, diffuse architecture, and localization in non-photoexposed areas. Group 2 (20%) showed activating STAT6 and CREBBP mutations, consistent CD23 and CD10 positivity, and exclusive presentation in sun-exposed sites. Group 3 (20%) shared a similar clinicopathological profile to Group 2 but was defined by TNFRSF14 mutations. Clonal origin and mutational evolution were studied in five patients, one with synchronous PCFCL and four with sequential samples from two PCFCL and 2 FL_CI. This analysis supports a model of PCFCL oncogenesis driven by circulating progenitors following complex evolutionary patterns, including convergent evolution and greater clonal diversity at relapse. Overall, our study refines the mechanisms driving PCFCL pathogenesis, while providing a framework for PCFCL differential diagnosis and clinical management.