Understanding Diffuse Large B-Cell Lymphoma: A Comprehensive Patient Guide

Table of Contents

• Introduction: What is DLBCL?
• How DLBCL is Diagnosed
• Molecular Types and Classification
• Who Gets DLBCL and Risk Factors
• Staging and Response Assessment
• Prognostic Factors and Survival Rates
• Treatment Approaches
• Long-Term Monitoring and Complications
• Future Directions and Research
• Source Information

Introduction: What is DLBCL?

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for approximately 30% of all cases. This aggressive cancer affects an estimated 150,000 people worldwide each year. Patients typically present with progressive lymph node enlargement (lymphadenopathy), disease outside the lymph nodes (extranodal disease), or both, and require prompt treatment.

The good news is that more than 60% of patients can be cured with standard immunotherapy called R-CHOP, which combines rituximab with four chemotherapy drugs: cyclophosphamide, doxorubicin, vincristine, and prednisone. However, patients whose disease doesn't respond to initial treatment or returns after treatment (refractory or relapsed disease) often face more challenging outcomes, though some can achieve long-term remission with secondary therapies.

Over the past two decades, researchers have made significant progress in understanding DLBCL's epidemiology, prognostic factors, and biological diversity. These advances have led to refined disease classification and the development of new treatment approaches that are increasingly personalized to individual patients' specific lymphoma characteristics.

How DLBCL is Diagnosed

Accurate diagnosis of DLBCL requires detailed examination of tumor tissue, best obtained through an excisional biopsy (removing an entire lymph node) evaluated by an expert blood cancer pathologist (hematopathologist). Beyond microscopic examination, proper lymphoma classification requires specialized tests including immunohistochemistry (staining for specific proteins), flow cytometry (analyzing cell characteristics), fluorescence in situ hybridization (FISH genetic testing), and molecular testing.

Fine-needle aspiration biopsies are inadequate for diagnosis, and core needle biopsies (removing a tissue sample with a larger needle) are often insufficient for complete evaluation. Core biopsy should only be performed when excisional biopsy isn't feasible. The updated World Health Organization (WHO) classification system has refined how we categorize these lymphomas, which represent a diverse collection of clinical and pathological entities.

Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) is the most common subtype, accounting for the majority of cases. This review focuses primarily on this category, though it's important to recognize that even within this classification, there's significant biological diversity that affects treatment response and outcomes.

Molecular Types and Classification

Gene expression profiling has identified two distinct molecular subtypes of DLBCL: the germinal center B-cell-like (GCB) subtype and the activated B-cell-like (ABC) subtype. Approximately 10-15% of cases are unclassifiable. These subtypes arise from different stages of B-cell development and rely on separate cancer-causing mechanisms.

The ABC subtype has significantly worse outcomes, with approximately 40-50% of patients experiencing 3-year progression-free survival compared to 75% with the GCB subtype. The ABC subtype is characterized by chronic B-cell receptor signaling and activation of nuclear factor κB (a protein complex that controls DNA transcription), while the GCB subtype expresses genes typically found in germinal center B cells, including BCL6 and EZH2.

While gene expression profiling isn't routinely performed in clinical practice, immunohistochemistry-based algorithms like the Hans algorithm can approximate these subtypes by classifying cases as GCB or non-GCB (which includes ABC and most unclassifiable cases). However, these methods risk misclassification. New molecular classification systems (LymphGen and DLBCL clusters) are emerging that may better define biological subtypes and enable more targeted treatments.

Genetic testing can also identify specific rearrangements with clinical significance. A MYC rearrangement is found in 12% of cases, while concurrent rearrangements of MYC with BCL2, BCL6, or both occur in 4-8% of cases. These "double-hit" or "triple-hit" lymphomas are now classified as high-grade B-cell lymphomas and are associated with poor outcomes after standard R-CHOP treatment.

Additionally, approximately 45% of DLBCL cases show overexpression of MYC protein, and 65% show overexpression of BCL2 protein. When both proteins are overexpressed (occurring in about 30% of cases), this "double-expressor lymphoma" is associated with worse prognosis than cases with single or no overexpression of these proteins.

Who Gets DLBCL and Risk Factors

The median age at DLBCL diagnosis is in the mid-60s, with 30% of patients being older than 75 years. While most patients have no history of lymphoma, DLBCL can sometimes develop from transformation of an underlying low-grade B-cell lymphoma. Research suggests DLBCL has a complex, multifactorial cause involving:

• Genetic factors: Multiple genetic susceptibility loci have been identified through genome-wide association studies
• Viral infections: Epstein-Barr virus (EBV), HIV, human herpesvirus 8 (HHV8), hepatitis B, and hepatitis C
• Immune system disorders: Solid-organ transplantation, autoimmune disorders (systemic lupus erythematosus, Sjögren's syndrome, celiac disease), and other immunodeficiencies
• Lifestyle and environmental factors: Increased body mass index in young adults, agricultural pesticide exposure, ionizing radiation
• Protective factors: Allergies (including hay fever), alcohol consumption, vegetable consumption, and sun exposure appear to decrease risk

No routine screening procedures are currently available for DLBCL. Type 2 diabetes does not appear to significantly affect DLBCL risk.

Staging and Response Assessment

Staging follows the Ann Arbor system and Lugano classification criteria. PET-CT (positron emission tomography with computed tomography) has largely replaced CT alone due to its higher sensitivity for detecting active lymphoma. The total metabolic tumor volume at diagnosis may also provide prognostic information.

Bone marrow biopsy is positive in 15-20% of cases. When concordant large B cells are present (meaning the same type of lymphoma cells found elsewhere), this is associated with poorer prognosis. However, bone marrow biopsy is no longer mandatory for patients who undergo PET-CT staging, though it might occasionally miss low-volume disease or different types of indolent lymphoma.

End-of-treatment response evaluation is best performed using PET-CT interpreted according to the Deauville five-point scale, with scores of 1-2 (and probably 3) indicating complete metabolic response. While interim PET-CT after 2-4 treatment cycles can provide prognostic information, changing treatment based solely on these findings hasn't been shown to improve outcomes and isn't recommended outside clinical trials.

Circulating tumor DNA shows promise as a less invasive method for monitoring treatment response and is being actively investigated. Routine surveillance imaging after completed treatment hasn't been shown to affect outcomes and is generally discouraged.

Prognostic Factors and Survival Rates

The International Prognostic Index (IPI) remains the primary clinical tool for predicting outcomes. The refined National Comprehensive Cancer Network IPI (NCCN-IPI) provides even better discrimination among high-risk patients. Molecular features also significantly impact prognosis:

Patients with the ABC subtype have approximately 40-50% 3-year progression-free survival compared to 75% for the GCB subtype. Double-hit or triple-hit lymphomas (with MYC and BCL2 and/or BCL6 rearrangements) have particularly poor outcomes with standard R-CHOP treatment. Double-expressor lymphomas (overexpression of both MYC and BCL2 proteins) also have worse prognosis than cases without this pattern.

Research tracking 3,082 patients with newly diagnosed DLBCL treated with R-CHOP shows that the risk of disease progression is highest within the first 2 years after diagnosis, followed by a lower but persistent risk for up to 10 years. Patients who remain event-free for 2 years have overall survival nearly matching that of the general age-matched population.

Treatment Approaches

R-CHOP remains the standard frontline treatment, curing more than 60% of patients. This regimen combines:

1. Rituximab (monoclonal antibody targeting CD20)
2. Cyclophosphamide (chemotherapy)
3. Doxorubicin (chemotherapy)
4. Vincristine (chemotherapy)
5. Prednisone (steroid)

For double-hit or triple-hit lymphomas, more intensive therapies like dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with rituximab) may be associated with better outcomes and are currently recommended in appropriate cases.

Patients with treatment failure after R-CHOP often have poor outcomes, particularly those with disease refractory to initial or subsequent therapies. However, some patients can achieve durable remission and even cure with secondary treatments, including:

• Salvage chemotherapy regimens
• Stem cell transplantation
• Chimeric antigen receptor (CAR) T-cell therapy
• Novel targeted agents

The development of targeted therapies that work preferentially in specific molecular subtypes represents an exciting advancement in DLBCL treatment. These include agents targeting B-cell receptor signaling, nuclear factor κB pathway, EZH2, and other specific vulnerabilities in lymphoma cells.

Long-Term Monitoring and Complications

Patients should be clinically monitored every 3 months for the first 2 years after diagnosis, then every 6-12 months. Those who remain event-free for 2 years have excellent long-term prospects, with survival rates approaching those of the general population.

However, physicians should monitor for long-term risks, including:

• Late infectious complications
• Autoimmune disorders
• Secondary cancers
• Cardiovascular events (particularly related to chemotherapy effects)

These late effects highlight the importance of long-term follow-up care even after successful lymphoma treatment. Patients should maintain relationships with their oncology team and primary care physicians to address these potential issues proactively.

Future Directions and Research

The past two decades have seen remarkable progress in understanding DLBCL's biological diversity. New molecular classification systems (LymphGen and DLBCL clusters) are helping researchers identify distinct biological entities within what was previously considered a single disease.

These advances are paving the way for more personalized treatment approaches targeting specific molecular vulnerabilities. Current research focuses on:

• Developing reproducible molecular assays for clinical use
• Validating new classification systems
• Testing targeted therapies in specific molecular subgroups
• Improving outcomes for high-risk subtypes
• Developing less toxic treatment approaches
• Exploring immunotherapy options beyond rituximab

The integration of circulating tumor DNA analysis for response assessment and monitoring represents another promising area of investigation that may lead to less invasive management strategies.

Source Information

Original Article Title: Diffuse Large B-Cell Lymphoma
Authors: Laurie H. Sehn, M.D., M.P.H. and Gilles Salles, M.D., Ph.D.
Publication: The New England Journal of Medicine, March 4, 2021
DOI: 10.1056/NEJMra2027612

This patient-friendly article is based on peer-reviewed research published in one of the world's leading medical journals. It maintains all significant findings, statistics, and clinical information from the original paper while making the content accessible to educated patients and caregivers.