Lymphoma

Lymphomas are generally classified as Hodg-kin's and non-Hodgkin's (NHL) lymphomas, although there are a number of subtypes of NHL that differ in their cellular morphology, response to chemotherapy, and prognosis. The new cases annually in the United States are in the range of 7300 for Hodgkin's disease and 56,000 for non-Hodgkin's.3 Deaths due to NHL are about 20,000 annually, whereas only about 1400 deaths occur from Hodgkin's disease in the United States. Globally, about 62,000 cases of Hodgkin's disease occur annually, but over 280,000 cases of NHL occur annually, predominantly in more developed countries.36

The strongest known risk factors for NHL are chromosomal translocations, the inciting cause for which isn't usually clear. Viral infection, e.g., with Epstein-Barr virus, human herpes virus 8, or human T-lymphotropic virus-1 (HTLV-1), and acquired immunodeficiencies due to AIDS or immunosuppressive drugs, for example, have been suggested as causative.

The molecular pathogenesis oflymphomas has been well studied.37 Because tissue is readily available and distinct genetic events such as chromosomal translocations are clearly related to disease progression, it has been easier to study such events in lymphomas and leukemia than in solid tumors such as lung, breast, and colon. Chromosomal translocations are often the inciting events in lymphomas, in contrast to solid tumors, where gene deletions are more common. The translocation events often involve the im-munogloblin (Ig) loci and a proliferative or anti-apoptotic gene such as BCL-2. About one-sixth of all NHLs have translocations of the BCL-6 gene that encodes a transcriptional repressor of normal B-lymphocyte differentiation.37 This favors cell proliferation and decreased cell senescence. Some NHLs have translocations that lead to overexpression of c-myc and D-type cyclins, which favor cell proliferation. A type of NHL called mantle cell lymphoma (MCL) exhibits a genomic deletion of the cell cycle checkpoint gene p16 (INK4A) or a genomic amplification of the gene bmi-1 that codes for a repressor of the p16 (INK4A) locus. Both of these alterations lead to loss of cell cycle checkpoint control. Still other lymphomas lose cell genome integrity by deletion or mutation of the ATM or p53 genes.

These genetic alterations are summarized in Figure 3-7. A number of these genetic lesions involve pathways that will be seen again in other cancers.

Gene expression microarrays are now being employed to molecularly categorize a number of human cancers. One of the first practical demonstrations of this was for NHL. Alizadeh et al.38 showed that diffuse large B-cell lymphomas (DLBCL) can be categorized by prognosis using gene arrays. Although clinical parameters can also predict survival, gene expression arrays are independent and perhaps more reliable predictors of prognosis. Furthermore, gene expression profiles of subgroups of DLBCL demonstrate that they are pathogenetically distinct diseases.

Lymphomas are as a class generally responsive to chemotherapy. The advent of the Mustargen (nitrogen mustard), Oncovin (vincristine), prednisone, procarbazine (MOPP) regimen by De Vita and colleagues39 and subsequent variations on this theme have led to a high cure rate for Hodgkin's lymphoma. In general, NHLs are also responsive to combination chemotherapy, although somewhat less so than Hodgkin's c-myc translocation BL, DLBCL c-myc mutations BL, DLBCL c-myc transcription ABC DLBCL cyclin D1 translocation MCL

cyclin D2 transcription

ABC DLBCL cyclin D3 translocation B-NHL

Ink4a deletion/bmi-1 amplification MCL

BCL-6 translocation B-NHL

Pax5 translocation LPCL, B-NHL

Cell Growth and Proliferation

Differentiation Block

BCL-2 translocation FL, GCB DLBCL BCL-2 amplification

DLBCL BCL-2 transcription ABC DLBCL, MCL, SLL/CLL NFKB2 translocation

DLBCL, CTCL BCL10 translocation MZL

API2-MALT1 translocation MZL kBa mutations HD

IkB kinase activity ABC DLBCL, HD EBV LMP1 PTLD, HD HTVL-1 tax ATL

ALK translocation ALCL

p53 mutation/deletion NHL

Ink4a deletion/bmi-1 amplification MCL

ATM mutation/deletion MCL, SLL/CLL

Figure 3-7. Pathogenetic mechanisms in lymphomas. Arrows indicate presumptive target genes and pathways affected by oncogenic events in various lymphoma types. An enhanced version of this figure with references is available as Supplemental Figure S1 at http://www.cancercell.org/cgi/content/full/2/5/ 363/DC1. Abbreviations: ALCL, anaplastic large-cell lymphomia; ATL, adult T-cell lymphoma; BL, Burkitt's lymphoma; B-NHL, B-cell non-Hodgkin's lymphoma; CLL, chronic lymphocytic leukemia; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; FL, follicular lymphoma; GCB, germinal-center B cell; HD, Hodgkin's disease; LPCL, lymphoplasmacytoid lymphoma; MZL, marginal zone lymphoma; PTLD, post-transplant lymphoproliferative disorder; SLL, small lymphocytic lymphoma. (From Staudt and Wilson,37 reprinted by permission from Elsevier.)

Genomic Instability

Figure 3-7. Pathogenetic mechanisms in lymphomas. Arrows indicate presumptive target genes and pathways affected by oncogenic events in various lymphoma types. An enhanced version of this figure with references is available as Supplemental Figure S1 at http://www.cancercell.org/cgi/content/full/2/5/ 363/DC1. Abbreviations: ALCL, anaplastic large-cell lymphomia; ATL, adult T-cell lymphoma; BL, Burkitt's lymphoma; B-NHL, B-cell non-Hodgkin's lymphoma; CLL, chronic lymphocytic leukemia; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; FL, follicular lymphoma; GCB, germinal-center B cell; HD, Hodgkin's disease; LPCL, lymphoplasmacytoid lymphoma; MZL, marginal zone lymphoma; PTLD, post-transplant lymphoproliferative disorder; SLL, small lymphocytic lymphoma. (From Staudt and Wilson,37 reprinted by permission from Elsevier.)

lymphoma. Development of monoclonal antibodies such as rituximab target lymphoma cell surface receptors and are showing responses in chemoresistant NHLs.

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