What does this research mean for the field?

In PTCL-NOS, the cutaneous microenvironment drives a distinct, hyperproliferative malignant phenotype characterized by NF-κB and IL-17 activation, which contrasts with the immune evasion and metabolic stress signatures found in blood-derived lymphoma cells. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This case report aims to characterize the unique molecular mechanisms contributing to cutaneous aggressiveness in PTCL-NOS.

May 30, 2026Open Access

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

Key Points

This case report aims to characterize the unique molecular mechanisms contributing to cutaneous aggressiveness in PTCL-NOS.
Single-cell RNA sequencing (scRNA-seq) was performed on skin lesions and peripheral blood from a patient diagnosed with PTCL-NOS.
Copy number variation analysis was conducted to assess clonal expansion across skin and blood compartments.
Skin-resident malignant T cells displayed hyperproliferative phenotypes and activated NF-κB and IL-17 signaling pathways.
Blood-derived lymphoma cells exhibited immune evasion signatures and markers of metabolic stress.
The patient remained refractory to multiple chemotherapy regimens and died six months post-diagnosis.

Abstract

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.

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