Transcriptional landscape of nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma: tumor microenvironment and checkpoint genes

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B-cell malignancy with an indolent course, yet some cases relapse or transform to Tcell/ histiocyte-rich large B-cell lymphoma (THRLBCL). Biological factors underlying poor outcomes in NLPHL are largely unknown, and the relationship between THRLBCL and untransformed NLPHL has not been systematically defined. We analyzed 178 NLPHL and 22 THRLBCL cases using whole-transcriptome RNA sequencing and clinical data. NLPHL patients were younger, had limited-stage disease, and better outcomes than THRLBCL patients. Variant immuno-architectural patterns (IAP) in NLPHL showed THRLBCL-like transcriptional profiles, especially with splenic involvement and high Lymphocyte-Predominant International Prognostic Score (LP-IPS). In-silico deconvolution of the tumor microenvironment (TME) revealed B-cell enrichment in classic NLPHL, intermediate profiles in variant NLPHL, and increased activated CD4+ and CD8+ T-cells and macrophages in THRLBCL. Higher follicular helper T-cell content was associated with shorter event-free survival in an exploratory analysis. NLPHL cases showed strong B-cell and T-helper signatures, whereas THRLBCL cases were enriched for macrophage and cytotoxic T-cell pathways and expressed higher immune checkpoint genes, suggesting an immunosuppressive TME. Signatures defined a spectrum from classic to variant NLPHL and THRLBCL. External validation in independent cohorts reproduced this gradient, supporting a continuous microenvironmental spectrum spanning NLPHL and THRLBCL.