What is B-cell lymphoma?

What is B-Cell Lymphoma?

B-cell lymphoma is a heterogeneous group of malignant neoplasms arising from B-lymphocytes at various stages of differentiation, ranging from precursor B-cells to mature B-cells, classified according to the WHO classification system into numerous distinct subtypes with varying clinical behaviors, prognoses, and treatment approaches. 1

Classification Framework

B-cell lymphomas are broadly divided into two major categories according to the WHO classification 1:

• Precursor B-cell neoplasms: Precursor B-lymphoblastic leukemia/lymphoma, representing immature B-cell malignancies 1

• Mature B-cell neoplasms: A diverse group including chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, mantle cell lymphoma, marginal zone lymphomas, and plasma cell neoplasms 1

Key Subtypes and Their Characteristics

Diffuse Large B-Cell Lymphoma (DLBCL)

DLBCL is the most common subtype of non-Hodgkin lymphoma worldwide and represents the prototype of aggressive B-cell lymphomas. 2, 3, 4

• Cell characteristics: Medium-sized cells with scant cytoplasm, round vesicular nuclei, and prominent nucleoli (often 2 nucleoli adherent to the nuclear membrane) with numerous mitoses 1

• Phenotype: Mature B-cell markers (CD19, CD20, CD23) with surface immunoglobulin expression 1

• Molecular features: Clonal mature B-cell with immunoglobulin heavy and light chain gene rearrangements 1

• Cell of origin subtypes: Germinal center B-cell (GCB) and activated B-cell (ABC) subtypes exist with distinct biology and prognosis, where ABC DLBCL has substantially worse outcomes 5

• Morphologic variants: Centroblastic, immunoblastic, anaplastic large B-cell, T-cell/histiocyte-rich, plasmablastic, and lymphomatoid granulomatosis-type 1

Follicular Lymphoma

• Grading system: Grade 1 (0-5 centroblasts/hpf), Grade 2 (6-15 centroblasts/hpf), Grade 3 (>15 centroblasts/hpf with subgrades 3a and 3b) 1

• Cell composition: Mixed population of centrocytes (cleaved cells) and centroblasts (large cells with prominent nucleoli) resembling germinal center cells 1

• Genetic marker: Human follicular lymphoma is regularly associated with t(14;18) chromosomal translocation involving BCL2 1

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Diagnostic criteria: Requires absolute lymphocytosis >5,000 mature-appearing lymphocytes/µL in peripheral blood 1

• Immunophenotype: CD19+, CD20+, CD23+, CD5+ (in absence of other pan-T-cell markers), with monoclonal surface immunoglobulin of low density 1

• Morphology: Mature-appearing lymphocytes, though admixtures with up to 55% prolymphocytes remain consistent with CLL diagnosis 1

Other Important Subtypes

• Burkitt's lymphoma: Highly aggressive with morphologic variants (classical, atypical, with plasmacytoid differentiation) and clinical subtypes (endemic, sporadic, immunodeficiency-associated) 1

• Mantle cell lymphoma: Includes blastoid variant 1

• Marginal zone lymphomas: Extranodal MALT type, nodal (monocytoid B cells), and splenic variants 1

Diagnostic Approach

Immunophenotypic studies are essential for diagnosis of most B-cell lymphoma subtypes, particularly peripheral T-cell lymphomas, diffuse large B-cell lymphomas, and precursor B-cell lymphoblastic lymphoma/leukemia. 1

Required Diagnostic Elements

• Anatomic site specification and tissue type (lymph node versus extranodal) 1

• Histological tumor type according to WHO classification 1

• Immunophenotyping: All markers investigated (both positive and negative) should be specified using CD nomenclature, identifying which cell population expresses each antigen 1

• Molecular studies: When performed, diagnostic implications must be stated in the report 1

• Specimen adequacy: Explicitly state if precise diagnosis is limited by specimen quality (needle biopsy, necrotic/fibrotic tissue) 1

Clinical Heterogeneity and Biological Complexity

B-cell lymphomas display significant clinical, pathologic, and biologic heterogeneity that impacts prognosis and treatment selection. 2, 6, 4

• Double-hit lymphomas: Approximately 5-10% of DLBCL cases with concurrent MYC plus BCL2 (or BCL6) chromosomal rearrangements, associated with aggressive behavior and poor prognosis 5

• Double-expressor lymphomas: Overexpress MYC and BCL2 protein, also associated with poor outcomes 5

• Immune dysregulation: B-cell lymphomas are accompanied by broad immune regulatory disorders including autoimmunity, hyperinflammation, immunodeficiency, and increased infection risk 6

Treatment Implications

Rituximab (anti-CD20 antibody) is FDA-approved for treatment of various CD20-positive B-cell lymphomas including relapsed/refractory low-grade or follicular NHL, previously untreated follicular NHL, diffuse large B-cell NHL, and chronic lymphocytic leukemia. 7

• Standard therapy: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) remains the mainstay for DLBCL, achieving long-term disease control in nearly 90% of limited-stage and up to 60% of advanced-stage patients 3

• Molecular subtype-directed therapy: Advances in molecular characterization provide foundation for personalized therapy based on GCB versus ABC subtype, with ongoing trials evaluating risk-adapted approaches 5, 3