Immunohistochemical and Molecular Biomarkers in Diffuse Large B-Cell Lymphoma: A Systematic Review of Diagnostic, Prognostic, and Therapeutic Implications

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell non-Hodgkin lymphoma worldwide. Although R-CHOP immunochemotherapy has improved outcomes, relapse and refractory disease remain substantial challenges. Emerging immunohistochemical and molecular biomarkers may improve risk stratification and precision management. This systematic review synthesized evidence published between 2021 and 2026 on emerging biomarkers in DLBCL, focusing on their diagnostic, prognostic, predictive, and therapeutic relevance and whether they provide clinically meaningful information beyond conventional cell-of-origin classification and the International Prognostic Index. Methods PubMed/MEDLINE, Web of Science Core Collection, and Cochrane CENTRAL were systematically searched, supplemented by Consensus-guided literature discovery, grey-literature searching, and manual reference screening. Forty-three studies were synthesized narratively using the Synthesis Without Meta-analysis (SWiM) framework. Results Cell-of-origin classification remained clinically relevant, but did not consistently outperform the International Prognostic Index. Loss of BCL6 expression and a Ki-67 proliferation index above 70% showed independent prognostic value. Next-generation sequencing identified seven molecular subtypes with distinct biological and prognostic profiles. Tumour-microenvironment markers, including VSIG4- and CD163-positive macrophages, CD8-positive lymphocytes, CD11c-positive dendritic cells, and immune-checkpoint ligands, were associated with survival. Liquid-biopsy markers, particularly early molecular response assessed by circulating tumour DNA, demonstrated promising predictive value. Conclusion Integrated biomarker profiling combining immunohistochemistry, molecular classification, tumour-microenvironment characterization, and liquid-biopsy monitoring may enhance risk stratification and precision management of DLBCL. Prospective validation is required before routine clinical implementation.