The search for meaningful prognostic markers in diffuse large B-cell lymphoma.

The diagnosis and classification of non-Hodgkin lymphoma has undergone substantial change during the last 20 years. We have moved from a purely morphologically driven classification system to one in which immunophenotype and molecular genetic features are now part of the disease definitions. This has permitted us to define new entities such as mantle cell lymphoma, anaplastic large cell lymphoma, and extranodal marginal zone lymphoma. Despite much progress, we still recognize that many disease entities are heterogeneous. For example, several studies have demonstrated the t(14;18) (characteristic of follicular lymphoma [FL]) in a substantial minority of diffuse large B-cell lymphomas (DLBCLs),1-4 suggesting that DLBCL encompasses more than one entity. Nonreproducible morphologic criteria have helped to place the Revised European American Classification of Lymphoid Neoplasms (REAL classification) provisional entity of Burkittlike lymphoma into the melting pot of DLBCL in the upcoming World Health Organization classification.5 Although B-cell immunoblastic lymphoma was discarded in the REAL classification, some maintain that it should be separated from DLBCL with centroblastic features.6 Immunophenotyping of DLBCL, even with a limited panel of markers commonly used in lymphoma diagnosis, also reveals multiple patterns.7 This heterogeneity also is reflected in the clinical behavior of DLBCL. While 50% to 60% of patients with DLBCL are cured with anthracycline-containing regimens, 40% to 50% of patients are not cured. To assist in the clinical stratification of patients with these lymphomas, the international prognostic index (IPI) was developed and has proven to be a very useful tool for clinicians in predicting outcomes of patient groups based on a limited set of clinical and laboratory variables.8 Although host factors measured by the IPI must be considered important, I believe that the IPI, at least in part, is a surrogate marker for as yet undefined biologic markers. As a testament to the importance that investigators have placed on finding prognostic biologic markers in DLBCL, numerous studies have been undertaken to find new markers that can identify patients who will not do well with current multiagent chemotherapy. Implied in this endeavor is the supposition that there are biologic differences between lymphomas that will independently affect the clinical outcome. In the current issue of the Journal, Uherova and colleagues9 describe a series of 28 patients with de novo DLBCL. Patients with histories of FL and cutaneous lymphomas were excluded from the study. In a univariate analysis, the authors report a shorter overall survival in patients with lymphomas expressing CD10 compared with those whose lymphomas lack this marker. This is one of the first studies to examine CD10 status as a prognostic factor in DLBCL. Others, cited by the authors in their article, also are recent, and survival also is compared by univariate analysis.7,10 Studies such as these raise important questions: (1) Are there accepted biologic markers that are independent prognostic factors in DLBCL? (2) How does the present study fit into published literature? (3) Might there be other markers that may prove superior to current markers, and how do we find them?