Advanced Insights Into the Biology of Malignant Lymphomas

This Journal of Clinical Oncology Review Series deals with some of the newest scientific advances that provide insight into the biology of malignant lymphomas and offers a future pathway for the development of targeted therapies. As described by Nogai et al, recent studies of tumor tissue from patients with diffuse large B-cell lymphoma have demonstrated heterogeneity in the gene expression profiles that has resulted in the classification of these lymphomas into at least three different categories: germinal center B-cell lymphoma, activated B-cell lymphoma, and mediastinal B-cell lymphoma. The remaining lymphomas are currently classified as other, and remain heterogeneous. Different signaling pathways seem to be activated in each of these different categories. Furthermore, specific activating mutations have been detected, particularly in the activated B-cell lymphomas. These activated pathways have been shown to be critical for the survival of these lymphoma cells and are therefore likely targets for successful future intervention. In contrast, in Hodgkin’s disease, the role of the tumor microenvironment has been shown to have significant prognostic importance. InteractionswiththeReed-Sternbergcellandthesurroundinginflammatory infiltrate are critical for the pathogenesis of Hodgkin’s lymphoma. This is discussed in detail in the article by Steidl et al. Several areas of great clinical controversy are also described in this series of articles. Transformation of indolent lymphomas to diffuse large B-cell lymphomas is a critical event that requires intensive successful intervention to prevent a fatal outcome. As discussed by Montoto and Fitzgibbon, many questions remain about the biology and treatment of this process. Is it prevented or delayed by early therapeutic intervention? What is the histology and natural history of recurrence after successful treatment for transformation? The biology, diagnosis, and appropriate treatment of the highly proliferative, aggressive non-Hodgkin’s lymphoma in the adult patient have been controversial for many years. Classic Burkitt’s lymphoma is relatively easy to diagnose. However, many tumors demonstrate histologic features of both Burkitt’s lymphoma and diffuse large B-cell lymphoma. The so-called double-hit lymphomas fall into this category. In the newest classification, these have been called gray-zone lymphomas, as discussed by Salaverria and Siebert. Perhaps no new diagnostic test has had more impact on the treatment of malignant lymphomas than the positron emission tomography (PET) scan that is now in widespread use. In this Review Series, Cheson provides a detailed review of the data regarding the usefulness of PET scans in different histologies. In addition, the use of interim and post-treatment PET scans has become relatively common. The value of these scans in predicting ultimate therapeutic benefit may vary greatly depending on both the timing of the scan and the histology of the lymphoma. Three new approaches to treatment are discussed in extensive detail in the Review Series. Chakraverty and MacKinnon describe the development of the reduced-intensity allogeneic stem-cell transplantation that has made allogeneic transplantation available to many patients who previously did not have a match or were too old to survive the procedure. Despite the failure of the randomized trials of anti-idiotype therapy to provide significant benefit for patients with follicular lymphoma, new approaches are being developed, as described by Brody et al. As information regarding the importance of the tumor microenvironment in regulating the growth of malignant lymphoma increases, the potential for successful immunotherapy also increases. In the treatment of patients with malignant lymphoma, there has never been a time when more novel therapeutics are being developed. What are the rational targets? What are the features of a novel agent that make it likely to succeed? How can we move forward with a rational plan for the development of the most important of these agents? This subject is also addressed extensively in the article by Mahadevan and Fisher. Finally, as we become more successful and a greater number of patients survive longer, the long-term impact of treatments becomes more of a problem for the cancer survivor and his or her physician. General guidelines for the follow-up of patients who have been treated for malignant lymphomas is proposed by Ng et al; however, much more study is necessary. In summary, we hope that this Journal of Clinical Oncology Review Series will provide the reader with information that is useful in the day-to-day management of these patients as well as a framework with which to understand the future biologic and treatment advances that we all believe will dramatically change the prognosis of patients with malignant lymphomas in the next decade.