Cutaneous extranodal NK/T cell lymphoma: heterogeneity of spatial transcriptomic profiling according to primary tumor site

Abstract

Introduction: Extranodal NK/T-cell lymphoma (ENKTL) with cutaneous involvement can be divided into primary cutaneous ENKTL (pcENKTL) and secondary cutaneous involvement (scENKTL). Despite different originations, the clinical and histopathological findings are indistinguishable. Moreover, the prognosis determinants in each entity have yet to be established. We investigated differences in spatially resolved transcriptome profiles between pcENKTL and scENKTL. Materials and methods: Seven samples with 24 regions of interest were selected for pcENKTCL and scENKTL, using CD56 and CD3 morphology markers. Results: In CD56-positive tumor cell areas, we detected 91 upregulated differentially expressed genes (DEGs) and 27 downregulated DEGs in pcENKTL compared with scENKTL. Protein–protein interaction network revealed significant enrichment of interferon signaling, T cell receptor signaling, and programmed cell death in pcENKTL. Moreover, significant enrichment of translation pathways and nonsense-mediated decay in scENKTL was observed. In immune cell areas, myeloid dendritic cell (p = 0.044) and M1 macrophage (p = 0.039) numbers were increased in pcENKTL. Conversely, neutrophil (p = 0.030) and M2 macrophage (p = 0.030) numbers were increased in scENKTL. We found an increased immune response and antigen presentation in pcENKTL with complete remission, while pcENKTL with progressive disease showed increased angiogenesis. Alternatively, scENKTL with long survival showed increased HLA expression and CD8 memory T cells and M1 macrophages, while scENKTL with short survival showed increased cancer-associated fibroblasts and BIRC5. Conclusion: Overall, the differences in transcriptomic expression and tumor microenvironment between pcENKTL and scENKTL, as well as subgroups based on the prognosis could widen our understanding of the biological characteristics of ENKTL. © 2025 Elsevier B.V., All rights reserved.