Clonal evolution of mycosis fungoides into peripheral T-cell lymphoma: evidence from next-generation sequencing in...

Cutaneous T-cell lymphomas (CTCL) are characterized by marked clinical and molecular heterogeneity. Mycosis fungoides (MF), the most common subtype, usually follows an indolent course but may rarely progress into more aggressive lymphoid neoplasms. Distinguishing between clonal evolution and the development of a second, unrelated lymphoma remains a diagnostic challenge, particularly when conventional T-cell receptor (TCR) gene rearrangement analysis is inconclusive. We report two patients with long-standing, clinically stable MF who subsequently developed rapidly progressive systemic disease with histologically confirmed peripheral T-cell lymphoma (PTCL). In both cases, TCR-gamma PCR analysis suggested distinct clonal populations across different biopsy sites. However, next-generation sequencing (NGS) using a comprehensive lymphoma-targeted gene panel revealed overlapping mutational profiles between skin and lymph node samples, supporting a shared clonal origin. These findings highlight the limitations of PCR-based clonality assessment and demonstrate the added value of NGS in defining clonal relationships and disease evolution in CTCL. Improved molecular characterization may have important implications for diagnosis, classification, and therapeutic decision-making in patients with T-cell lymphomas.