The indolent lymphomas as a group remain an enigma for both clinicians and pathologists. These malignancies are among the most sensitive to low-dose oral alkylating agents, radiotherapy, and steroids. However, although the overwhelming majority of patients with advanced-stage indolent lymphomas achieve a very good partial remission, far fewer patients achieve lasting complete remission and few, if any, are cured using conventional aggressive combination chemotherapy. This dichotomy between sensitivity to treatment on the one hand, yet incurability on the other has transformed the indolent lymphomas into an area of extremely active research at both the basic molecular level and in clinical trials.
Fundamental to a scientific approach that can form the basis for an understanding of the mechanism(s) whereby this dichotomy arises is a rational grouping of these disease entities, based not only on their appearance under the microscope but also on their immunophenotype, cytogenetics and molecular characteristics. The Revised European-American Lympoma (REAL) classification is an attempt to define pathologic entities based on these characteristics and also hopefully to have some clinical relevance.
The accompanying manuscript describes the indolent lymphomas in the categories defined within the REAL classification and outlines the pathologic and clinical features of each group. The manuscript provides an almost encyclopedic, up-to-date review of the field. Included within the indolent lymphomas, for the purposes of this review, is mantle cell lymphoma, which the authors themselves admit is for almost purely historical reasons. Mantle cell lymphoma is no longer normally classified as indolent, due to both its aggressive clinical course and its poor response to therapy.
Novel Treatment Strategies
There is widespread agreement that new treatment approaches are necessary for patients with indolent lymphoma. Although the authors reviewed the results of many recent chemotherapy trials, commentary on novel treatment approaches for these diseases was missing. Many of these novel treatments are immunotherapeutic approaches. They include the use of unlabeled monoclonal antibodies with or without chemotherapy, monoclonal antibodies labeled with radioisotopes, and vaccination strategies to induce T-cell-mediated immune responses against tumors. Although as yet there are no data suggesting that these approaches provide the necessary next step required for cure in these diseases, preliminary evidence intimates that these treatments produce results encouraging enough to merit discussion.
The Question Not Addressed
Although the authors extensively review the results of clinical trials performed to date, they avoid the issue of why cure so seldom occurs in these patients, despite their apparent chemosensitivity. Malignancies such as follicular lymphoma are characterized by molecular abnormalities that result in dysregulation of proteins involved in the life or death of a cell. All the indolent lymphomas die readily under ex vivo culture conditions, yet at least some population of lymphoma cells remain alive in vivo despite the use of chemotherapy. It is likely that complex interactions occur between receptors on the lymphoma cells and their ligands present within the tumor cell microenvironment. Such interactions could result in upregulation of proteins, making these cells more resistant to apoptosis and allowing at least a proportion of the malignant cells to survive chemotherapy. It is to be hoped that a more detailed analysis of the molecular basis of these diseases may explain, at least somewhat, why these diseases have been so difficult to cure in the face of their apparent chemosensitivity.
Which Way Forward?
With so many treatment approaches available for the indolent lymphomas and with therapeutic options for the individual patient ranging from watch and wait to bone marrow transplantation, it is clear that, despite many years of clinical trials, we remain unsure of which direction to take in these diseases. In the present manuscript, the authors have provided an excellent map to guide us through what we have learned about this disease. Hopefully this will provide a path to treatment approaches based on recognition of distinct clinicopathologic entities, with therapy tailored to the underlying malignant transforming event. A problem in this patient group remains the very long period of follow-up required to determine whether any new treatment approaches have an effect on the natural history of the disease. Therefore, it may be many years before we are able to determine which is truly the way forward, or alternatively, are we again back at the beginning?