Biology and Management of Diffuse Large B-cell Lymphoma

Julio Chavez, MD et al
Published: Friday, Mar 04, 2011
Recent statistics show lymphoid malignancies to be the fifth most common cause of cancer-related death in the United States. In 2009, nearly 65,980 new cases of non-Hodgkin lymphoma (NHL) were diagnosed and 19,500 patients died despite currently available treatments.1 Diffuse large B-cell lymphoma (DLBCL), the most common type of NHL in the Western Hemisphere, accounts for 30% to 40% of all NHL cases diagnosed annually in the United States.2

DLBCL typically afflicts patients in their sixth decade of life; primary mediastinal DLBCL variant, however, primarily afflicts women in their late 20s or early 30s. The incidence of DLBCL has increased in the past few decades, and this trend is independent of the human immunodeficiency virus (HIV) epidemic.3

CLASSIFICATION OF DLBCL

Revisions in the pathological classification of lymphomas in the past 30 years or so have resulted in several variations in DLBCL nomenclature. It had been called diffuse histiocytic lymphoma(Rappaport’s classification), centroblastic lymphoma(Kiel’s classification), and large cleaved follicular center cellor large cell immunoblastic lymphoma(National Cancer Institute).4,5

Recently, the Revised European and American Lymphoma classification defined DLBCL as a specific disease. Within this classification, however, it is still heterogeneous, manifesting a variety of morphological features (eg, anaplastic, Burkitt’s-like), protein and gene expression patterns, and clinical presentations (eg, primary mediastinal or central nervous system [CNS] lymphomas). Studies of gene expression profiling (GEP) contributed greatly to our understanding of DLBCL biology. GEP studies identified and validated 3 different subtypes of DLBCL—germinal center B-cell (GCB), activated B-cell (ABC), and primary mediastinal lymphoma (PML)—all with significant differences in terms of prognosis, progression-free survival (PFS), and overall survival (OS).6-8

GCB-DLBCL, apparently derived from germinal center B cells, is driven primarily by deregulation of apoptosis by BCL6 and responds well to rituximab-based immunochemotherapy. ABC-DLBCL is believed to be driven by high levels of nuclear factor kappa-B (NFκB) activity and is associated with worse outcomes despite immunochemotherapy. PML shares GEP signatures similar to those of patients with classical Hodgkin’s lymphomas and is associated with a better prognosis than other DLBCL subtypes. Treatment-related toxicities remain a concern, even without the use of involved-field radiation therapy (IF-XRT), and are being addressed in clinical trials.

PATHOLOGICAL AND CLINICAL CHARACTERISTICS OF DLBCL

Morphologically, DLBCL is characterized by large B cells with a high proliferation index resembling that of germinal centroblasts. DLBCL usually develops de novo, but can emerge as a clonal transformation in patients with low-grade lymphomas or chronic lymphocytic leukemia (CLL). De novo DLBCL tends to respond better to standard therapy and has a better prognosis than transformed DLBCL. Several morphologic variants of DLBCL have been described: centroblastic, immunoblastic, plasmablastic, T-cell/histiocyte-rich, and anaplastic B-cell lymphoma (usually anaplastic lymphoma kinase–positive).9,10 While pathological evaluation can distinguish between these variants, their prognostic significance remains controversial.

Immunophenotype studies demonstrate that DLBCL co-expresses pan B-cell markers, including CD19, CD20, CD79a, CD45RA, and the nuclear transcription factor PAX5. The expression of additional markers may have prognostic implications. The proliferation factor Ki67 is usually high, with a mean percentage of 65. High Ki67 levels (>80%) have been associated with shorter OS.11 The germinal center–associated marker CD10 is expressed in 30% to 40% of cases, and BCL6 is expressed in 60% of cases. Retrospective studies have associated BCL6 expression with prolonged PFS and OS following rituximab-based immunochemotherapy.12,13 Only 10% of DLBCL cases express CD5, which has been associated with shorter survival. The expression of CD5 should raise suspicion of transformation from a more indolent form of NHL, such as small lymphocytic lymphoma (SLL) or CLL.14

Information obtained from genetic studies of DLBCL tumor specimens stresses the complexity of the disease’s biology. DLBCL expresses clonally rearranged IgH genes with somatic mutations in the variable region. Thus, it is thought that DLBCL cells are derived from antigen-exposed B cells. No single gene abnormality is pathognomonic of DLBCL. Recurrent translocations involving BCL6, BCL2, and MYC genes had been described in about 50% of cases. Chromosomal translocation leading to upregulation of BCL2 [t(14;18)] is present in 20% to 30% of DLBCL cases and specially observed GCB variants. Gene abnormalities in ABC-DLBCL are more complex and include trisomies, deletions, and chromosomal inactivation.15,16


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