Diffuse Large B-cell Lymphoma (DLBCL) is an aggressive, fast-growing form of non-Hodgkin lymphoma, representing the most common lymphoid malignancy in adults. This cancer originates from B-lymphocytes, a type of white blood cell. Understanding DLBCL has evolved toward molecular subtyping, which reveals significant biological diversity within the disease. This classification is fundamental to patient management as it identifies two major subtypes: Germinal Center B-cell-like (GCB) DLBCL and Activated B-cell-like (ABC) DLBCL (also called non-GCB). The GCB subtype is defined by a gene expression pattern that closely resembles normal B-cells found within the germinal center of lymph nodes. This cell-of-origin distinction predicts treatment response and influences the long-term outlook.
Classification and Molecular Basis of GCB DLBCL
The classification of GCB DLBCL is rooted in the “cell of origin” concept, linking the lymphoma to a specific stage of normal B-cell development. Germinal centers (GCs) are temporary structures within lymph nodes where B-cells rapidly multiply and undergo somatic hypermutation. GCB DLBCL arises from B-cells that mimic those found in the GC, specifically those in the light zone where selection occurs.
This cellular origin dictates the distinct molecular profile of GCB DLBCL. The malignant cells characteristically express genes normally found in GC B-cells, such as BCL6 and CD10. The BCL6 gene, a transcriptional repressor, is often rearranged or mutated, promoting cell proliferation. Furthermore, up to 45% of GCB cases feature a chromosomal translocation, t(14;18), which causes the overexpression of the anti-apoptotic protein BCL2, contributing to tumor growth.
The gold standard for identifying the GCB subtype is Gene Expression Profiling (GEP), a laboratory technique that analyzes the activity of thousands of genes simultaneously. GEP provides a detailed molecular fingerprint, confirming the cell-of-origin classification. Since GEP can be technically demanding and costly, most clinical settings rely on a surrogate method called Immunohistochemistry (IHC). IHC uses antibodies to stain for the presence or absence of proteins like CD10, BCL6, and MUM1 to predict the molecular subtype.
Clinical Significance of Subtyping
Knowing the cell-of-origin subtype holds significant clinical importance due to its strong association with prognosis and response to therapy. Patients diagnosed with GCB DLBCL generally have a more favorable outlook compared to those with the Activated B-cell-like (ABC) subtype.
The underlying molecular differences explain this variation in clinical behavior. ABC DLBCL is often driven by the constitutive activation of the NF-κB survival pathway, a feature largely absent in GCB DLBCL. This difference means the two subtypes are biologically distinct diseases. While GCB DLBCL responds better to standard chemoimmunotherapy, a subset of GCB cases, particularly those with translocations involving MYC and BCL2 (known as “double-hit” lymphoma), are highly aggressive and carry a poor prognosis. The classification serves as a powerful prognostic tool that helps clinicians estimate the likelihood of cure with initial treatment.
Diagnosis, Testing, and Disease Staging
The diagnostic process for GCB DLBCL begins with obtaining a tissue sample, typically through a core needle or excisional biopsy of the enlarged lymph node or tumor mass. This sample is then examined by a pathologist to confirm the presence of large, abnormal B-cells. Once DLBCL is confirmed, the tissue is subjected to specialized testing to determine the cell-of-origin subtype.
The most common method for subtyping is Immunohistochemistry (IHC), frequently using the Hans algorithm. This algorithm evaluates the expression of three proteins—CD10, BCL6, and MUM1—on the tumor cells to categorize the lymphoma as GCB or non-GCB. While convenient for routine clinical use, the IHC method has a misclassification rate of approximately 20% when compared to the molecular gold standard, GEP. More advanced molecular testing, such as Fluorescence In Situ Hybridization (FISH), is performed to detect specific chromosomal abnormalities like the MYC and BCL2 translocations that define high-risk subtypes.
Following diagnosis and subtyping, the disease extent is determined through staging. Staging is typically performed using positron emission tomography-computed tomography (PET/CT) scans, which identify all sites of active disease. The Ann Arbor staging system classifies the disease extent, ranging from Stage I (involvement of a single lymph node region or organ site) to Stage IV (widespread involvement). A bone marrow biopsy may also be performed to check for lymphoma involvement in the bone marrow, informing treatment decisions.
Standard Treatment Protocols
The standard initial treatment for most newly diagnosed DLBCL patients, including those with the GCB subtype, is a combination regimen known as R-CHOP. This protocol combines the monoclonal antibody Rituximab with four chemotherapy drugs: Cyclophosphamide, Doxorubicin, Vincristine, and the steroid Prednisone. Rituximab targets the CD20 protein found on the surface of B-cells, marking them for destruction by the immune system.
R-CHOP is administered in cycles, typically every 21 days for a total of six cycles, though duration may vary based on the disease stage. For patients with localized disease (Stage I or II), a shorter course of R-CHOP followed by consolidation radiation therapy to the affected area is sometimes used. Given the favorable prognosis of GCB DLBCL, R-CHOP is highly effective, leading to a cure in a large proportion of patients.
In certain high-risk situations, such as for patients with double-hit lymphoma, a more intensive regimen called dose-adjusted R-EPOCH may be considered. R-EPOCH involves the same drugs as R-CHOP, plus Etoposide, administered as a continuous infusion with dose adjustments based on blood counts. If the lymphoma relapses after initial treatment, subsequent therapies, including high-dose chemotherapy followed by stem cell transplant or newer options like CAR T-cell therapy, are explored.