Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal subtype of DLBCL characterized by unique clinicopathological features and an increased risk of central nervous system (CNS) relapse. Due to its low incidence, comprehensive investigations into its biological characteristics have remained limited.At the 2026 European Hematology Association (EHA) Congress, the team led by Professor Huilai Zhang from Tianjin Medical University Cancer Institute and Hospital presented an integrated analysis of the clinical characteristics, genomic landscape, and immune microenvironment of PB-DLBCL. By comparing PB-DLBCL with nodal DLBCL and immune-privileged site lymphomas, the study provides one of the most comprehensive biological portraits of this rare disease entity to date.
During the meeting, Oncology Frontier – Hematology Frontier invited Dr. Junlei Jia, first author of the study, to discuss how these findings may reshape risk stratification, long-term surveillance, and individualized treatment strategies for PB-DLBCL.
Defining PB-DLBCL as a Distinct Biological Entity
Oncology Frontier – Hematology Frontier:
Primary breast DLBCL is a relatively rare extranodal lymphoma, and its biological features have not been systematically characterized. Your team’s integrated analysis revealed unique clinical outcomes, genomic alterations, and immune microenvironment features. How do these findings reshape our understanding of PB-DLBCL?
Dr. Junlei Jia:
From a clinical perspective, PB-DLBCL demonstrates a survival pattern distinct from nodal DLBCL. Although patients often achieve satisfactory disease control during the early treatment period, they continue to face a persistent risk of relapse and disease-related mortality over the long term. This suggests a unique pattern of disease evolution.
At the molecular level, PB-DLBCL does not simply mirror the genomic profile of nodal DLBCL. Instead, we observed enrichment of both the MCD and EZB molecular subtypes, accompanied by abnormalities involving the B-cell receptor (BCR)/NF-κB signaling pathway and epigenetic regulatory mechanisms. These findings suggest a distinct biological pathogenesis.
Within the tumor microenvironment, PB-DLBCL is characterized by a predominance of B cells, relatively limited immune-cell infiltration, and substantial tumor-cell heterogeneity. These features may contribute to the persistent long-term relapse risk observed in this disease.
Taken together, our study establishes a comprehensive clinical, genomic, and microenvironmental framework for PB-DLBCL and provides compelling evidence supporting its classification as a biologically distinct disease entity. These findings also create an important foundation for future molecularly guided risk stratification, precision therapy, and long-term disease management.
Implications for Precision Medicine and Risk Stratification
Oncology Frontier – Hematology Frontier:
Your study found that PB-DLBCL is predominantly characterized by MCD and EZB subtypes, with enrichment of mutations such as PIM1 and NOTCH2, along with a unique immune microenvironment. How might these molecular findings influence future risk stratification and personalized treatment strategies?
Dr. Junlei Jia:
These findings indicate that PB-DLBCL is not a homogeneous disease. Therefore, future risk stratification should move beyond traditional approaches based solely on the International Prognostic Index (IPI) or cell-of-origin (COO) classification and incorporate molecular subtype information together with key genomic alterations.
For patients with the MCD subtype, frequent activation of the BCR/NF-κB pathway suggests that BTK inhibitors may represent a promising targeted therapeutic option.
For those with the EZB subtype, epigenetic dysregulation may provide opportunities to explore treatments such as EZH2 inhibitors and DNA methyltransferase inhibitors.
In addition, the unique immune microenvironment observed in PB-DLBCL—characterized by B-cell predominance and limited immune infiltration—suggests that future immunotherapy strategies should consider both tumor-intrinsic molecular characteristics and microenvironmental features to maximize therapeutic precision.
Long-Term Surveillance and Individualized Management
Oncology Frontier – Hematology Frontier:
An important finding from your study is that although PB-DLBCL patients often experience favorable early outcomes, their long-term prognosis appears inferior to that of nodal DLBCL, with certain genetic alterations associated with disease progression. Based on these observations, what should be the key priorities for future monitoring and personalized treatment?
Dr. Junlei Jia:
First, surveillance strategies should be adapted to reflect the persistent long-term relapse risk associated with PB-DLBCL. Even patients who achieve excellent early treatment responses require prolonged follow-up.
Particularly beyond five years after treatment, clinicians should pay close attention to extranodal relapse patterns. In addition to routine lymph node evaluation, surveillance should specifically include potential recurrence sites such as the breast and central nervous system.
Patients presenting with high-risk clinical features—including bulky disease, bilateral breast involvement, elevated IPI scores, or high-risk genomic alterations—should undergo more intensive follow-up.
Second, risk stratification models should incorporate molecular information alongside traditional clinical variables. Integrating genomic alterations with established prognostic factors may improve identification of patients at elevated risk for late relapse.
Third, individualized treatment approaches deserve further investigation. Patients harboring high-risk molecular features may benefit from precision-based consolidation or maintenance strategies.
Within our study cohort, a small number of patients received immunochemotherapy combined with BTK inhibitors followed by maintenance BTK inhibitor therapy. Although the sample size and follow-up duration currently limit definitive conclusions, maintenance approaches tailored to specific molecular profiles remain an important area for future research.
Overall, our findings suggest that PB-DLBCL management should evolve from a primary focus on short-term response assessment toward a broader strategy centered on long-term relapse risk management. Ultimately, the goal is to establish a truly personalized monitoring and treatment framework driven by molecular characteristics.
Conclusion
This comprehensive analysis highlights PB-DLBCL as a biologically unique subtype of diffuse large B-cell lymphoma with distinctive clinical behavior, molecular architecture, and immune microenvironment features.
The enrichment of MCD and EZB molecular subtypes, recurrent alterations involving PIM1 and NOTCH2, and the presence of a relatively immune-poor tumor microenvironment collectively support the need for precision-based management approaches. Importantly, the study demonstrates that favorable early treatment outcomes do not eliminate the risk of late relapse, emphasizing the necessity of long-term surveillance and risk-adapted care.
As molecular profiling becomes increasingly integrated into routine practice, PB-DLBCL may serve as an important model for the transition from traditional prognostic assessment toward truly personalized lymphoma management.
Expert Profiles
Professor Huilai Zhang
Tianjin Medical University Cancer Institute and Hospital
MD, Chief Physician, Doctoral Supervisor
Director, Department of Lymphoma
Professor Zhang specializes in the molecular diagnosis and individualized treatment of malignant lymphoma and serves in numerous national academic leadership positions, including Chair of the Lymphoma Committee of the Chinese Anti-Cancer Association.
He has published more than 90 scientific articles in leading international journals including Blood, Cancer Research, Journal of Experimental Medicine, Leukemia, and Blood Advances, and was honored with the Fourth National Physician Excellence Award.
Dr. Junlei Jia
Tianjin Medical University Cancer Institute and Hospital
PhD in Oncology
Mentor: Professor Huilai Zhang
Dr. Jia focuses on both basic and clinical lymphoma research. He has published multiple scientific papers, presented research at national and international conferences, and delivered an oral presentation at the 2026 European Hematology Association (EHA) Congress.
