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Chapter 76 Origin of Non-Hodgkin Lymphoma 1231

GCB DLBCL
Follicular lymphoma Burkitt lymphoma
BCL2 (t 14;18) c-MYC (t 8; 14)
ABC DLBCL Multiple myeloma
Antigen

NFkB
Pro–B cell Pre–B cell Naive mature B cell Plasmablast Plasma cell
Germinal center reaction
Mantle cell lymphoma AID Somatic hypermutation
Bone marrow hematopoiesis
BCL2
MYC
BCL6 NFkB
p21
p27
Fig. 76.1 CLASSIFICATION OF COMMON NON-HODGKIN LYMPHOMAS (NHLs) IN RELA-
TION TO B-CELL DEVELOPMENT IN GERMINAL CENTERS (GCs). Hematopoiesis results in B cell
precursors that ultimately produce immunoglobulin M (IgM) that recognize cognate antigen via activation of
recombinase activating genes (RAG1 and RAG2) and a GC reaction occurs. A regulatory program relying on
BCL6 regulation of cell proliferation and apoptosis occurs at this point, and rearrangements presumed to occur
along this course result in post-GC lymphomas, including follicular lymphoma, Burkitt lymphoma, and diffuse
large B-cell lymphoma (DLBCL). The underlying molecular biology of NHL subsets (and other lymphoid
neoplasms) reflects the GC step and other stages of B-cell development. For example, gene profiling of DLBCL
reveals that whereas activated B cell–like (ABC) DLBCL reflects the plasmablast stage along normal B-cell
development, multiple myeloma expression profiles more consistent with differentiated plasma cell origin.

result in dissemination of GC cells within lymph nodes. Thus, critical association with EBV has been noted for posttransplant
derangements in several different genes can result in abnormal GC lymphoproliferative disorder, a disease that occurs in the setting of
homeostasis and drive lymphoma formation; thus is a novel paradigm organ transplantation and immunosuppression targeting cellular
whereby dysregulation of B cell differentiation leads to transforma- immunity.
tion and lymphoma. Beyond these factors, the contributions of other modifiable risk
Regulation of antigen stimulation of the B-cell receptor (BCR) is factors and heredity appear to play only a small role in NHL develop-
also important in both B-cell maturation and the development of ment. Several environmental factors (pesticides, Agent Orange, radia-
NHL. The BCR consists of a multimeric signaling complex, includ- tion exposure) have been implicated in NHL, but the associations
ing CD79A and CD79B, which acts through the immunoreceptor between these agents and lymphomagenesis are difficult to prove
tyrosine activation motif on CD79B and leads to a cascade of and the effect size of these factors appears to be relatively small.
molecular events involving SYK and BTK signaling. The end-result Pesticide exposure does appear to have a dose-effect relationship
of this cascade is an increase in cellular proliferation through activa- with regard to NHL pathogenesis and has been linked to recur-
tion of NFκB target genes and other cellular machinery. Almost all rent t(14;18) cytogenetic rearrangements that are noted in DLBCL
NHLs express surface Ig, suggesting that functional BCR signaling and FL, but the percentage of cases linked to pesticide exposure in
is important at some point in the process of lymphoma formation. these entities is very low. Likewise, several genetic linkage studies
Analysis of Ig SHM patterns in lymphoma samples further suggests have found associations between several genes and the development
that antigen-induced selective pressure is important in the pathogen- of various lymphoma subtypes, but the role of variations in these
esis of NHL. The antigen(s) involved in this process are unknown, pathways in lymphomagenesis has not been validated. Thus, there
and it is also unclear whether ongoing antigen stimulation is impor- does appear to be inherited or modifiable risk factors that likely con-
tant in subsets of NHL. spire with other acquired genetic/molecular lesions in the origin of
Epidemiologic studies have bolstered the argument that chronic lymphoma.
immune activation and inflammation are connected with NHL And so, factors related to abnormal immune surveillance, chronic
development; these data also suggest that immune surveillance also inflammation, external exposures and host factors conspire to produce
plays a role in the origin of NHL. DLBCL and Burkitt lymphoma genetic/molecular lesions involved in lymphoma formation and
(BL) occur more frequently in immunocompromised hosts and are progression. The remainder of this review will focus on current
often Epstein-Barr virus (EBV)–positive. HIV/AIDS is a significant knowledge of biologic features of individual NHL subtypes.
risk factor for post-GC neoplasms, and this risk is attenuated with
the use of highly active antiretroviral therapy. For example, the risk
of central nervous system lymphomas is increased more than 1000- DIFFUSE LARGE B-CELL LYMPHOMA
fold in patients with AIDS. NHL also occurs more frequently in
acquired or inherited immunodeficiencies such as common variable Diffuse large B-cell lymphoma is the most common subtype of NHL
immunodeficiency and severe combined immunodeficiency and with (~25% of all NHL) and is responsible for more patient deaths than
solid organ and hemopoietic transplantation. Other clinical situa- any other form of lymphoma. This entity often presents at an
tions in which chronic infection or inflammation occurs have also advanced stage, and around 50% of all patients fail to respond long-
been linked to NHL. Gastric MALT (Helicobacter pylori), hepato- term to standard chemotherapy programs; the vast majority of those
splenic T-cell lymphoma (associated with infliximab use), and thyroid patients will eventually succumb to their disease. Even prior to the
NHL (Hashimoto thyroiditis) are specific instances in which the availability of gene expression profiling technology, it was clear clini-
development of lymphoid malignancy can be traced to chronic cally (based on tumor morphology, immunohistochemical staining,
inflammation, either of microbial or autoimmune etiology. Finally, a and patient outcomes) that DLBCL is a heterogeneous disease.