DiagnosisandTreatmentForHighRiskofDLBCL
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Tong-Yu Lin
Cancer Center , Sun Yat-sen University , Guangzhou , China
The most common type of lymphoma in adults, diffuse large-B-cell lymphoma, has an annual incidence in the United States of more than 25,000 cases and accounts for 30 to 40 percent of cases of non-Hodgkin's lymphomas (NHL). Combination chemotherapy has transformed diffuse large-B-cell lymphoma from a universally fatal disease to a potentially curable one, but less than half of all patients are cured. It accounts for approximately one third of the total number of adult NHL patients. The International Prognostic Index (IPI), a well-established predictor of outcome in diffuse large-B-cell lymphoma, is based on five clinical characteristics (age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites). However, the outcome in patients with diffuse large-B-cell lymphoma who have identical IPI values varies considerably. New molecular methods may make risk-adjusted therapies possible for diffuse large-B-cell lymphoma in a way similar to the current practice in acute leukemia [1] .
Factors Relative to Prognosis of DLBCL
Initially grouped into the intermediate prognostic grade by the International Working Formulation (IWF), DLBCL is recognized as a distinct entity by the Revised European-American Lymphoma and WHO classifications. However, patients with DLBCL have highly variable outcomes reflecting a heterogeneous group of tumors with different genetic abnormalities, clinical features, response to treatment, and prognosis. Combination chemotherapy containing anthracyclines has transformed DLBCL from a universally fatal disease to a potentially curable one. Although most patients respond to initial anthracycline-based therapy, fewer than half are cured. Identification of patients who do not benefit from current treatment may constitute the basis for risk-adjusted therapies for DLBCL. It could also lead to identification of patients who maybe candidates for investigational approaches, and allow examination whether new therapeutic approaches improve the outcome of high-risk patients without confounding the study population with patients who benefit from the standard therapy. Several factors are related to prognosis of DLBCL, including pathogenetic subgroup, staging, prognostic factors and particular site [2] .
Gene Expression Profiling of DLBCL
Recent application of genome-wide gene expression profiling analysis by DNA array technology further confirmed the presence of ontogenetically distinct DLBCL subtypes: GC-like DLBCL and non-GC-like DLBCL. GC-like DLBCL harbors the expression pattern of genes characteristic of normal GC B-cells (GC signature genes). Non-GC-like DLBCL consists of activated B-cell (ABC) -like DLBCL and "type 3" subtypes. The ABC-like tumors express genes characteristic of in vitro activated peripheral blood B-cells (activated B-cell signature genes) as well as some genes normally expressed by plasma cells, thus suggesting their post-GC origin. Type 3 is a heterogeneous DLBCL subtype that does not express high levels of either the GC or ABC set of genes. Notably, gene expression-defined GC-like DLBCL demonstrated the presence of Ig gene intraclonal heterogeneity whereas tumors exhibiting an ABC-like gene expression profile did not. Gene expression-defined DLBCL subtypes not only correspond to derivation from distinct stages of lymphocyte ontogeny but also likely represent different mechanisms of malignant transformation and distinct tumor biology (Fig 1). The t(14;18)(q32;q21) translocation involving the BCL-2 gene and the amplification of the c-rel locus on chromosome 2p have been detected exclusively in GC-like DLBCL. High expression of nuclear factor B (NF-B) target genes has been observed in ABC-like DLBCL but not in GC-like DLBCL cell-lines. NF-B is usually retained in an inactive form in the cytoplasm, by binding to members of the IB family of proteins. In response to signaling through diverse pathways, members of the IB family are phosphorylated by the IB kinase complex (IKK) and subsequently are degraded by the ubiquitin-proteasome pathway. This leads to release of NF-B family members that translocate into the nucleus and activate transcription thus mediating proliferation, apoptosis and cell survival. ABC-like, but not GC-like, DLBCL, exhibit constitutive activity of IKK, the inhibition of which is cytotoxic to ABC-like but not to GC-like DLBCL cell lines [3] .
There are a variety of techniques for analyzing microarray data, but the two general types are unsupervised and supervised. With the unsupervised approach, microarray data are analyzed without the use of external information such as clinical data or survival time. In contrast, with the supervised approach, the aim is to identify genes whose expression correlates with some external variables. With both unsupervised4 and supervised methods, microarray studies of diffuse large-B-cell lymphomas showed that gene-expression signatures were associated with clinical outcomes.
Role of PET in Diagnostic Imaging
The majority of studies evaluating the role of PET in the diagnostic staging of lymphoma are retrospective in nature and often attempt to compare PET with other imaging modalities. In those studies, biopsies of questionable lesions are almost never performed and, usually, the interpretation of the PET scan is not "blinded," meaning nuclear medicine physicians had access to multiple other imaging results while reading the PET images, resulting in the potential for bias. Despite these limitations, PET is clearly emerging to have a significant role in the diagnostic evaluation of lymphoma, particularly diffuse large B-cell lymphoma and Hodgkin's disease. Small studies also suggest that the initial management of patients with lymphoma in clinical practice frequently changes based upon PET scan findings [4] .
Fig 1 Molecular, pathogenetic and clinical features distinguishing germinal-center-like and activated B-cell-like diffuse large B-cell lymphoma.......（后略) ......
Tong-Yu Lin
Cancer Center , Sun Yat-sen University , Guangzhou , China
The most common type of lymphoma in adults, diffuse large-B-cell lymphoma, has an annual incidence in the United States of more than 25,000 cases and accounts for 30 to 40 percent of cases of non-Hodgkin's lymphomas (NHL). Combination chemotherapy has transformed diffuse large-B-cell lymphoma from a universally fatal disease to a potentially curable one, but less than half of all patients are cured. It accounts for approximately one third of the total number of adult NHL patients. The International Prognostic Index (IPI), a well-established predictor of outcome in diffuse large-B-cell lymphoma, is based on five clinical characteristics (age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites). However, the outcome in patients with diffuse large-B-cell lymphoma who have identical IPI values varies considerably. New molecular methods may make risk-adjusted therapies possible for diffuse large-B-cell lymphoma in a way similar to the current practice in acute leukemia [1] .
Factors Relative to Prognosis of DLBCL
Initially grouped into the intermediate prognostic grade by the International Working Formulation (IWF), DLBCL is recognized as a distinct entity by the Revised European-American Lymphoma and WHO classifications. However, patients with DLBCL have highly variable outcomes reflecting a heterogeneous group of tumors with different genetic abnormalities, clinical features, response to treatment, and prognosis. Combination chemotherapy containing anthracyclines has transformed DLBCL from a universally fatal disease to a potentially curable one. Although most patients respond to initial anthracycline-based therapy, fewer than half are cured. Identification of patients who do not benefit from current treatment may constitute the basis for risk-adjusted therapies for DLBCL. It could also lead to identification of patients who maybe candidates for investigational approaches, and allow examination whether new therapeutic approaches improve the outcome of high-risk patients without confounding the study population with patients who benefit from the standard therapy. Several factors are related to prognosis of DLBCL, including pathogenetic subgroup, staging, prognostic factors and particular site [2] .
Gene Expression Profiling of DLBCL
Recent application of genome-wide gene expression profiling analysis by DNA array technology further confirmed the presence of ontogenetically distinct DLBCL subtypes: GC-like DLBCL and non-GC-like DLBCL. GC-like DLBCL harbors the expression pattern of genes characteristic of normal GC B-cells (GC signature genes). Non-GC-like DLBCL consists of activated B-cell (ABC) -like DLBCL and "type 3" subtypes. The ABC-like tumors express genes characteristic of in vitro activated peripheral blood B-cells (activated B-cell signature genes) as well as some genes normally expressed by plasma cells, thus suggesting their post-GC origin. Type 3 is a heterogeneous DLBCL subtype that does not express high levels of either the GC or ABC set of genes. Notably, gene expression-defined GC-like DLBCL demonstrated the presence of Ig gene intraclonal heterogeneity whereas tumors exhibiting an ABC-like gene expression profile did not. Gene expression-defined DLBCL subtypes not only correspond to derivation from distinct stages of lymphocyte ontogeny but also likely represent different mechanisms of malignant transformation and distinct tumor biology (Fig 1). The t(14;18)(q32;q21) translocation involving the BCL-2 gene and the amplification of the c-rel locus on chromosome 2p have been detected exclusively in GC-like DLBCL. High expression of nuclear factor B (NF-B) target genes has been observed in ABC-like DLBCL but not in GC-like DLBCL cell-lines. NF-B is usually retained in an inactive form in the cytoplasm, by binding to members of the IB family of proteins. In response to signaling through diverse pathways, members of the IB family are phosphorylated by the IB kinase complex (IKK) and subsequently are degraded by the ubiquitin-proteasome pathway. This leads to release of NF-B family members that translocate into the nucleus and activate transcription thus mediating proliferation, apoptosis and cell survival. ABC-like, but not GC-like, DLBCL, exhibit constitutive activity of IKK, the inhibition of which is cytotoxic to ABC-like but not to GC-like DLBCL cell lines [3] .
There are a variety of techniques for analyzing microarray data, but the two general types are unsupervised and supervised. With the unsupervised approach, microarray data are analyzed without the use of external information such as clinical data or survival time. In contrast, with the supervised approach, the aim is to identify genes whose expression correlates with some external variables. With both unsupervised4 and supervised methods, microarray studies of diffuse large-B-cell lymphomas showed that gene-expression signatures were associated with clinical outcomes.
Role of PET in Diagnostic Imaging
The majority of studies evaluating the role of PET in the diagnostic staging of lymphoma are retrospective in nature and often attempt to compare PET with other imaging modalities. In those studies, biopsies of questionable lesions are almost never performed and, usually, the interpretation of the PET scan is not "blinded," meaning nuclear medicine physicians had access to multiple other imaging results while reading the PET images, resulting in the potential for bias. Despite these limitations, PET is clearly emerging to have a significant role in the diagnostic evaluation of lymphoma, particularly diffuse large B-cell lymphoma and Hodgkin's disease. Small studies also suggest that the initial management of patients with lymphoma in clinical practice frequently changes based upon PET scan findings [4] .
Fig 1 Molecular, pathogenetic and clinical features distinguishing germinal-center-like and activated B-cell-like diffuse large B-cell lymphoma.......（后略) ......
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