Case Report: Cutaneous niche-restricted malignant phenotypes in PTCL-NOS revealed by single-cell sequencing.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) presenting with disseminated cutaneous involvement represents an aggressive disease subset with poor response to conventional chemotherapy and dismal prognosis. The tissue-specific molecular mechanisms driving cutaneous aggression remain poorly characterized at single-cell resolution. Here we report a 67-year-old male PTCL-NOS patient with hypertension and coronary artery disease history, presenting with generalized cutaneous nodules and rapid progression despite multi-line chemotherapy. Single-cell RNA sequencing (scRNA-seq) performed on paired skin lesions and peripheral blood at diagnosis revealed striking microenvironmental dichotomy: skin-resident malignant T cells exhibited hyperproliferative phenotypes (high CDC20B, HIST1H3B, MKI67+), activation of NF-κB and IL-17 signaling, and extensive crosstalk with endothelial cells; conversely, blood-derived lymphoma cells displayed immune evasion signatures and metabolic stress markers. Copy number variation analysis confirmed clonal expansion across both compartments with distinct tissue-specific transcriptional programs. Despite CHOP, CHOEP, DA-EPOCH, and AC-CHOP (azacitidine plus chidamide) regimens, the patient experienced primary refractory disease and died 6 months from diagnosis following COVID-19 superinfection. To our knowledge, this is the first case reporting single-cell transcriptomic comparison of skin versus blood compartments in PTCL-NOS, revealing how cutaneous microenvironment sculpts aggressive malignant phenotypes and providing potential targets for compartment-specific therapy.