Editor's Note: In 2025, the International Conference on Malignant Lymphoma (ICML) convened in Switzerland, bringing together the world's leading experts in the field of lymphoma. At the conference, Professor David W. Scott from the University of British Columbia, Canada, was honored with the prestigious Gianni Bonadonna Award for his outstanding contributions to the field of aggressive B-cell lymphoma. Professor Scott delivered a keynote lecture titled "Molecular Classification of Aggressive B-cell Lymphoma," systematically reviewing the evolution of classification from traditional pathology to multidimensional molecular markers. He also proposed a draft for a future classification framework integrating genomics, pointing the way forward for precision diagnosis and treatment in this field.Current Status and Challenges in the Classification of Aggressive B-cell Lymphoma
“The classification systems we currently use, whether the International Consensus Classification (ICC) or the 5th edition of the World Health Organization classification (WHO-HAEM5), begin with morphology and immunophenotype, which form the foundation of our diagnosis,” Professor Scott stated at the outset. Currently, fluorescence in situ hybridization (FISH) is used to detect rearrangements in the MYC, BCL2, and/or BCL6 genes, which allows for the identification of a subset of tumors as high-grade B-cell lymphoma. Although the existing classification systems include as many as 24 different entities of aggressive B-cell lymphoma, approximately 70-75% of cases in clinical practice are categorized as “Diffuse Large B-cell Lymphoma, Not Otherwise Specified (DLBCL, NOS).” This is a highly heterogeneous category, posing a significant challenge for precision therapy.
The Ideal Goal of Molecular Subtyping: Balancing Precision and Practicality
Professor Scott presented his vision for an ideal molecular subtyping system: “We want molecular subtyping to act like a prism, separating the complex spectrum of aggressive B-cell lymphoma into distinct, homogeneous entities. These entities should be defined by common and, preferably, targetable biological features, thereby making the diagnosis itself the ultimate predictive biomarker for selecting treatment.” He emphasized that an ideal classification system must meet several criteria: it must cover the vast majority of tumors, be widely applicable to formalin-fixed paraffin-embedded (FFPE) tissue samples used in routine clinical practice, have a rapid turnaround time to guide therapy, and be able to integrate all available technological tools to accurately identify different entities.
From Gene Rearrangements to Gene Expression Profiling: Deepening the Dimensions of Classification
The Renaissance of Cell-of-Origin (COO)
The lecture revisited the classic Cell-of-Origin (COO) classification, which uses gene expression profiling to divide DLBCL into two subtypes: Germinal Center B-cell-like (GCB) and Activated B-cell-like (ABC). Professor Scott noted that although past clinical trials of targeted therapies for the ABC subtype had failed to yield positive results, a subgroup analysis of the POLARIX study has injected new vitality into the clinical value of the COO classification. This study showed that the Pola-R-CHP regimen demonstrated a significant survival benefit in patients with the ABC subtype. Professor Scott revealed, “In Canada, it was based on this subgroup data that we successfully petitioned drug regulators to approve this regimen specifically for patients with ABC-subtype DLBCL confirmed by gene expression profiling, indicating that COO classification remains a cornerstone of our understanding and treatment of DLBCL.”
Dark Zone Lymphoma: An Emerging Concept with Poor Prognosis
Building on the COO classification, Professor Scott’s team has proposed “Dark Zone Lymphoma” as a new umbrella term. The gene expression signature of this type of lymphoma mimics that of B-cells in the dark zone of the germinal center. It not only includes all Burkitt lymphomas and approximately 80% of MYC/BCL2 double-hit lymphomas but also encompasses some high-grade B-cell lymphomas-NOS and about 15% of GCB-DLBCLs.
Biologically, Dark Zone Lymphoma is highly dependent on MYC-driven proliferation and anti-apoptotic mechanisms mediated by BCL2 and other factors, but it exhibits very low NF-κB signaling pathway activity and features an “immune-cold” tumor microenvironment. Clinical data indicate that patients with Dark Zone Lymphoma have an extremely poor prognosis following standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy. More concerning, preliminary data suggest that these patients also respond poorly to CAR T-cell therapy. Professor Scott stated, “We currently believe that intensified therapy may be a more rational strategy for these patients, and there is an urgent need to develop new therapies that can target their unique biological characteristics.”
Genetic Subtypes: A New Framework Towards Precision Therapy
In recent years, genetic classification algorithms based on gene mutations, copy number variations, and structural variations, such as LymphGen and DLBCL-class, have provided a more profound perspective for the precise stratification of DLBCL. Professor Scott explained, “These algorithms have identified multiple subtypes with unique biological features and prognostic significance, such as the MCD, BN2, and EZB subtypes. Interestingly, these genetic subtypes remain highly consistent at the time of tumor relapse, suggesting they may originate from a common progenitor cell, which provides important clues for understanding tumor evolution.”
The GUIDANCE-1 study is a prime example of putting this concept into practice. In this study, genetic subtyping was completed within the first cycle of R-CHOP therapy, and patients were subsequently assigned to corresponding “R-CHOP + X” targeted therapy arms based on their subtype. Preliminary results showed significant improvements in both Progression-Free Survival (PFS) and Overall Survival (OS) for these patients.
Integration and Outlook: Constructing a Future Classification System Guided by Genomics
At the end of his lecture, Professor Scott presented his draft concept for a future classification system for aggressive B-cell lymphoma. The draft proposes establishing new umbrella entities such as “Dark Zone Lymphoma” and “MCD DLBCL” to more accurately classify tumors that are currently ambiguously categorized. For example, the highly heterogeneous “high-grade B-cell lymphoma-NOS” could be parsed into more homogeneous subgroups based on molecular features—with some being assigned to Dark Zone Lymphoma (having mutation features similar to Burkitt lymphoma) and others potentially identified as the MCD subtype—thereby revolutionizing treatment strategies.
However, realizing this vision still faces numerous challenges, including: the harmonization of classification criteria, the development and validation of reliable and rapid testing methods, and addressing the issue of insufficient tissue from core needle biopsies in clinical practice. Professor Scott concluded, “Over the past 25 years, our understanding of the molecular basis of aggressive B-cell lymphoma has advanced at a tremendous pace. I believe that a classification system built around the biology of the lymphoma, capable of guiding the selection of treatment strategies, is the ultimate goal we as clinicians pursue. This requires our continuous efforts to coordinate among stakeholders, optimize technology, and ultimately prove through clinical trials that a new classification system can genuinely improve patient outcomes.”
Expert Perspective and Clinical Application Outlook
Professor David W. Scott’s lecture was not only a summary of his and his team’s remarkable research achievements but also a profound insight into the future development of the entire field of aggressive B-cell lymphoma. The integrated genomics-based classification system he advocates for inherits and advances the spirit of evidence-based medicine pioneered by Gianni Bonadonna, aiming to translate deep molecular understanding into clinically actionable precision medicine pathways. This forward-looking classification framework signals that the treatment of aggressive B-cell lymphoma will gradually move from “one-size-fits-all” chemotherapy regimens to a new era of “tailored” therapy based on individualized biological characteristics.
Source/Interview: Onco-Look / Onco-Times
