ENAGenomicsDepartment of Pathology, Hematopathology Section, University Hospital Schleswig-Holsteinhttps://www.ebi.ac.uk/ena/browser/view/PRJNA1020109Homo sapiensPrimary cutaneous CD4+ small or medium T-cell lymphoproliferative disorder (PCSM-LPD) is a clonal T-cell proliferation disease confined to the skin. PCSM-LPD shares expression of T-follicular T helper cell (Tfh) markers with various mature T-cell lymphomas. However, the benign presentation of PCSM-LPD contrasts the clinical behavior of other Tfh-lymphomas. The aim of our study was to delineate the molecular similarities and differences between PCSM-LPD and other Tfh-derived lymphomas, to explain the clinical behavior and to unravel possible pathological mechanisms. We performed targeted next generation sequencing of 19 genes recurrently mutated in T-cell neoplasms in n=17 PCSM-LPD with high and in n=21 PCSM-LPD with low tumor cell content. Furthermore, gene expression profiling was used to identify genes potentially expressed in the PD1+ neoplastic cells. Expression of some of these genes was confirmed in situ using multi-stain immunofluorescence. We found that PCSM-LPD rarely harbors mutations recurrently detected in other T-cell neoplasms. PCSM-LPD is characterized by the invariable expression of the T-cell receptor associated LCK protein. CD70 and its ligand CD27 are co-expressed on PD1+ PCSM-LPD cells, suggestive of auto-activation of the CD70 pathway. In conclusion, PCSM-LPD differs from disseminated lymphomas of Tfh origin by their mutation profile. Activation of CD70 signaling also found in cutaneous T-cell lymphoma represents a potential driver of neoplastic proliferation of this benign neoplasia of Tfh. Overall design: 10 PCSM-LPD primary samples and 5 patients diagnosed with pseudolymphomas were analyzed using NanoSting PanCancer Immune Profiling Panel (Human) covering 770 genesENAfalseGene expression of PCSM-LPDGene expression of PCSM-LPD2025-09-242023-11-08PRJNA1020109GSE2438199606