Prognosis in Follicular Lymphoma — It's in the Microenvironment
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《新英格兰医药杂志》
Considerable clinical heterogeneity and wide variation in survival among patients are characteristic of many B-cell lymphomas. Prognostic markers that predict the clinical behavior of such tumors with greater accuracy than is currently possible are urgently needed to permit management decisions based on the prognosis in individual cases. Moreover, the variable course of some types of B-cell lymphomas may indicate that they are actually a mixture of distinct cancers that are not distinguished by the current classification schemes. In recent years, several large-scale studies involving microarray-based gene-expression profiling have identified novel lymphoma subtypes and improved the accuracy of predictions of outcome. A major success was achieved in an analysis of diffuse large-B-cell lymphomas by Rosenwald and colleagues, who showed that gene-expression profiling can separate these lymphomas into at least three subtypes.1 The different gene-expression profiles of these subtypes suggest that they arise from distinct pathogenetic mechanisms and have dissimilar tumor-cell abnormalities. Each of the three subtypes was also associated with a different prognosis. In addition, a study involving mantle-cell lymphomas demonstrated that it is possible to identify a gene-expression signature largely on the basis of genes associated with cell proliferation; these signatures identified subgroups of patients whose median duration of survival differed from one another by more than five years.
In this issue of the Journal, Dave and colleagues (pages 2159–2169) present the results of a microarray study in which they aimed to develop a molecular predictor of survival and to identify biologic determinants of the clinical heterogeneity of follicular lymphoma, which accounts for about 20 percent of B-cell non-Hodgkin's lymphomas. This type of lymphoma has a widely variable clinical course: the duration of survival after diagnosis ranges from less than 1 year to more than 20 years. Dave and colleagues identified two signatures of coordinately regulated genes that together represented the best predictor of survival. When patients were grouped into quartiles on the basis of survival-predictor scores, patients in the top quartile had a median survival of 13.6 years, whereas those in the bottom quartile had a median survival of only 3.9 years. This grouping demonstrates the strong predictive power of the method. The results represent an important advance for risk stratification in follicular lymphoma.
Interestingly, the genes that best defined the prognostic signatures in follicular lymphoma were expressed primarily by T cells, macrophages, or dendritic cells, but not by the tumor cells themselves. This finding indicates that the aggressiveness of the disease is mainly determined by the cellular microenvironment of the lymphoma, and not by obvious differences in the gene-expression profiles of the malignant cells themselves, although the cellular microenvironment may well be influenced in important ways by the lymphoma cells. Thus, from the molecular standpoint, follicular lymphoma is clearly different from diffuse large-B-cell lymphomas and mantle-cell lymphomas, in which the prognostic signatures are based largely on genes expressed by the lymphoma cells.
The dominant influence of the cellular microenvironment on the prognosis of follicular lymphoma probably reflects the participation of immune cells in the biology and pathogenesis of this type of tumor. Indeed, other features of follicular lymphoma also indicate the importance of the cellular microenvironment. In follicular lymphoma, the histologic features resemble the structure of normal germinal centers and show a characteristic association of the lymphoma cells with helper T cells, follicular dendritic cells, and macrophages in the follicles (see Figure). The tumor cells, like normal germinal-center B cells, seem to need a close association and interaction with T cells and dendritic cells. Moreover, the macrophages that normally remove apoptotic germinal-center B cells are also likely to play a role in follicular lymphoma. The dependency of follicular lymphoma cells on their microenvironment is supported by the fact that these cells are very difficult to grow in vitro in the absence of stromal cells and without stimulation of the CD40 receptor, which is a main signaling pathway for interactions between B cells and T cells.
Figure. Cellular Interactions in Germinal Centers and Follicular Lymphoma.
Germinal centers are histologic structures in lymph nodes and other lymphoid organs that develop during immune responses and are composed primarily of B cells. In normal germinal centers (left panel), antigen-activated B cells undergo clonal expansion, and the genes of the variable region of their immunoglobulin are modified through the introduction of somatic mutations. B cells in which these mutations lead to improved affinity of the B-cell receptor for the immunizing antigen are positively selected by interaction with helper T cells and follicular dendritic cells. B cells that fail this selection process undergo apoptosis and are taken up by macrophages. Germinal centers usually harbor several independent proliferating B-cell clones. In follicular lymphoma, the tumor cells grow in a follicular pattern, and the same cellular components are found as are present in normal germinal centers, suggesting that cellular interactions similar to those in normal germinal centers occur (right panel).
That the growth of lymphoma cells (and hence probably also their clinical behavior) is not as autonomous as was generally thought is one of the main currents of research on B-cell lymphomas. For example, it has been known for a number of years that gastric mucosa–associated lymphoid-tissue (MALT) lymphomas are associated with infection by Helicobacter pylori and that such lymphomas can be cured in their early stages by elimination of the bacteria. In B-cell chronic lymphocytic leukemia (B-CLL), the identification of groups of cases with nearly identical rearrangements of genes of the variable region of immunoglobulin suggests that activation of the B-CLL cells by antigens (perhaps autoantigens) plays a decisive role in the pathogenesis of this leukemia. There is also evidence that expansion of the B-CLL clone is caused primarily by tumor cells proliferating in so-called pseudofollicles, in which the cells are in contact with T cells and dendritic cells.
The identification of the role of the cellular microenvironment in the prognosis of follicular lymphoma will certainly motivate further studies designed to improve our understanding of the way in which the cellular microenvironment influences the biology of follicular lymphoma. If the critical components of these interactions can be identified, such studies may also lead to new treatment options — for example, through the development of ways to interfere with the suspected growth-promoting functions of the helper T cells and dendritic cells.
Source Information
From the Institute for Cell Biology (Tumor Research), University of Duisburg–Essen Medical School, Essen, Germany.
References
Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937-1947.(Ralf Küppers, Ph.D.)
In this issue of the Journal, Dave and colleagues (pages 2159–2169) present the results of a microarray study in which they aimed to develop a molecular predictor of survival and to identify biologic determinants of the clinical heterogeneity of follicular lymphoma, which accounts for about 20 percent of B-cell non-Hodgkin's lymphomas. This type of lymphoma has a widely variable clinical course: the duration of survival after diagnosis ranges from less than 1 year to more than 20 years. Dave and colleagues identified two signatures of coordinately regulated genes that together represented the best predictor of survival. When patients were grouped into quartiles on the basis of survival-predictor scores, patients in the top quartile had a median survival of 13.6 years, whereas those in the bottom quartile had a median survival of only 3.9 years. This grouping demonstrates the strong predictive power of the method. The results represent an important advance for risk stratification in follicular lymphoma.
Interestingly, the genes that best defined the prognostic signatures in follicular lymphoma were expressed primarily by T cells, macrophages, or dendritic cells, but not by the tumor cells themselves. This finding indicates that the aggressiveness of the disease is mainly determined by the cellular microenvironment of the lymphoma, and not by obvious differences in the gene-expression profiles of the malignant cells themselves, although the cellular microenvironment may well be influenced in important ways by the lymphoma cells. Thus, from the molecular standpoint, follicular lymphoma is clearly different from diffuse large-B-cell lymphomas and mantle-cell lymphomas, in which the prognostic signatures are based largely on genes expressed by the lymphoma cells.
The dominant influence of the cellular microenvironment on the prognosis of follicular lymphoma probably reflects the participation of immune cells in the biology and pathogenesis of this type of tumor. Indeed, other features of follicular lymphoma also indicate the importance of the cellular microenvironment. In follicular lymphoma, the histologic features resemble the structure of normal germinal centers and show a characteristic association of the lymphoma cells with helper T cells, follicular dendritic cells, and macrophages in the follicles (see Figure). The tumor cells, like normal germinal-center B cells, seem to need a close association and interaction with T cells and dendritic cells. Moreover, the macrophages that normally remove apoptotic germinal-center B cells are also likely to play a role in follicular lymphoma. The dependency of follicular lymphoma cells on their microenvironment is supported by the fact that these cells are very difficult to grow in vitro in the absence of stromal cells and without stimulation of the CD40 receptor, which is a main signaling pathway for interactions between B cells and T cells.
Figure. Cellular Interactions in Germinal Centers and Follicular Lymphoma.
Germinal centers are histologic structures in lymph nodes and other lymphoid organs that develop during immune responses and are composed primarily of B cells. In normal germinal centers (left panel), antigen-activated B cells undergo clonal expansion, and the genes of the variable region of their immunoglobulin are modified through the introduction of somatic mutations. B cells in which these mutations lead to improved affinity of the B-cell receptor for the immunizing antigen are positively selected by interaction with helper T cells and follicular dendritic cells. B cells that fail this selection process undergo apoptosis and are taken up by macrophages. Germinal centers usually harbor several independent proliferating B-cell clones. In follicular lymphoma, the tumor cells grow in a follicular pattern, and the same cellular components are found as are present in normal germinal centers, suggesting that cellular interactions similar to those in normal germinal centers occur (right panel).
That the growth of lymphoma cells (and hence probably also their clinical behavior) is not as autonomous as was generally thought is one of the main currents of research on B-cell lymphomas. For example, it has been known for a number of years that gastric mucosa–associated lymphoid-tissue (MALT) lymphomas are associated with infection by Helicobacter pylori and that such lymphomas can be cured in their early stages by elimination of the bacteria. In B-cell chronic lymphocytic leukemia (B-CLL), the identification of groups of cases with nearly identical rearrangements of genes of the variable region of immunoglobulin suggests that activation of the B-CLL cells by antigens (perhaps autoantigens) plays a decisive role in the pathogenesis of this leukemia. There is also evidence that expansion of the B-CLL clone is caused primarily by tumor cells proliferating in so-called pseudofollicles, in which the cells are in contact with T cells and dendritic cells.
The identification of the role of the cellular microenvironment in the prognosis of follicular lymphoma will certainly motivate further studies designed to improve our understanding of the way in which the cellular microenvironment influences the biology of follicular lymphoma. If the critical components of these interactions can be identified, such studies may also lead to new treatment options — for example, through the development of ways to interfere with the suspected growth-promoting functions of the helper T cells and dendritic cells.
Source Information
From the Institute for Cell Biology (Tumor Research), University of Duisburg–Essen Medical School, Essen, Germany.
References
Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937-1947.(Ralf Küppers, Ph.D.)