High-Resolution Spatial Transcriptomic Characterization of Syncytial Variant of Nodular Sclerosis Classical Hodgkin Lymphoma.

The syncytial variant of nodular sclerosis classical Hodgkin lymphoma (SV-NSCHL) is associated with inferior outcomes. However, the complexity of tumor microenvironment (TME) in SV-NSCHL is poorly understood. Therefore, we aimed to depict and compare the TME among SV-NSCHL and common nodular sclerosis classical Hodgkin lymphoma (cNSCHL). Using Xenium In Situ spatial transcriptomics on 20 regions of interest from 10 specimens (4 cNSCHL, 4 SV-NSCHL, and 2 reactive lymph nodes), we profiled 317,762 cells to map tumor intrinsic characteristics and spatially resolved immune ecosystems. The paternally expressed gene (PEG10) was among the top unregulated genes of Hodgkin and Reed-Sternberg (HRS) cells in SV-NSCHL. Immunohistochemistry (IHC) analysis in an independent cohort (n = 121) confirmed significantly higher PEG10 protein expression in HRS cells from SV-NSCHL and association with proliferation hallmarks. Patients with high PEG10 expression in NSCHL exhibited inferior progression-free survival (PFS), and multivariate analysis identified PEG10 as an independent prognostic factor. Besides, SV-NSCHL demonstrated a distinctly immunosuppressive microenvironment characterized by depletion and functional dampening of CD8+ T cells, expansion and higher immunosuppression scores of regulatory T cells (Tregs), altered B cell dynamics, and enrichment of M2-like macrophages with reduced phagocytosis and antigen presentation. Furthermore, although overall ligand-receptor crosstalk was attenuated in SV-NSCHL, specific inhibitory ligand-receptor interactions were preserved and upregulated between HRS cells and Tregs. Collectively, our study provided the first comprehensive spatial atlas of SV-NSCHL. It implicated PEG10 as a candidate contributor to HRS cell proliferation and identified actionable immune evasion signatures, offering a roadmap for targeted therapeutic interventions.