Advances in understanding and treating hematologic malignancies have provided a paradigm for advances in other cancers. Over the past 20 years, we have seen important advances in the classification, diagnosis, staging, prognosis, and treatment of patients with lymphomas.
Historical Background
Before reviewing the current status of our understanding of lymphomas and our ability to manage patients with these disorders, it is instructive to remember the situation in this field 20 years ago. The Working Formulation for classifying non-Hodgkin's lymphomas was published in 1982[1] and was replacing the Rappaport classification[2] and Lukes-Collins classification[3] in the United States. Although the Working Formulation was a melange of the concepts and terms of the Rappaport classification, Lukes-Collins classification, and Kiel classification,[4] it was never adopted as widely in Europe as in North America. The Kiel classification developed by Dr. Karl Lennert and colleagues remained widely used throughout Europe. However, the fact that the major journals in hematology/oncology demanded the use of the Working Formulation in publications eventually led to its predominance in published research.
In 1986, the diagnosis of subtypes of non-Hodgkin's lymphomas was not nearly as accurate as most clinicians believed.[5-8] A high degree of inter- and intraobserver variability was found in studies of pathologists' ability to make reproducible diagnoses. The chance that the specific subtype of non-Hodgkin's lymphoma could be reproduced by another pathologist was not much more than 50%. This obviously had huge implications for interpreting clinical publications. This state of affairs probably reflected the lack of widespread use of sophisticated immunophenotyping, frequent lack of access to cytogenetics, and the diverse definitions of lymphoma subtypes that were in use.
In 1986, the Ann Arbor Staging system[9] was the most widely utilized approach to categorizing patients for risk and for choosing therapy. However, in that year, papers began to appear suggesting that it was possible to use other factors in addition to the Ann Arbor system to better predict outcome and select patients for therapy.[10,11] While computed tomography (CT) scans were widely utilized, postiron-emission tomography (PET) scans had not been introduced, and gallium scanning—the most widely available functional imaging method—proved problematic in other than the most experienced hands. Although still widely used in Hodgkin's disease, staging laparotomies were much less often used in staging patients with non-Hodgkin's lymphoma.
The optimal treatment for patients with "diffuse large cell lymphoma" was a point for debate in 1986. The CHOP regimen (cyclophosphamide, doxorubicin(Drug information on doxorubicin) HCl, vincristine [Oncovin], prednisone(Drug information on prednisone)) had been described a decade earlier, and this therapy or its variants were widely used. However, several new "third-generation" regimens including m-BACOD (methotrexate, bleomycin, doxorubicin [Adriamycin], cyclophosphamide(Drug information on cyclophosphamide), Oncovin, dexamethasone(Drug information on dexamethasone)), ProMACE-MOPP (prednisone, methotrexate(Drug information on methotrexate), Adriamycin, cyclophosphamide, etoposide, mechlorethamine, Oncovin, procarbazine(Drug information on procarbazine) [Matulane], prednisone), and MACOP-B (methotrexate, Adriamycin, cyclophosphamide, Oncovin, prednisone, bleomycin(Drug information on bleomycin)) were widely suspected of being superior to CHOP.
Patients with follicular lymphoma and those with small lymphocytic lymphoma were often treated initially with chlorambucil(Drug information on chlorambucil) (Leukeran). The very intensive programs that are used today to treat Burkitt's lymphoma and lymphoblastic lymphoma were widely utilized in pediatrics but had not become as accepted in treating adults. Many of the subtypes of lymphoma that today provide a focus for therapeutic clinical research had not yet been described.
Classification of Non-Hodgkin's Lymphoma
In 1994, a group of hematopathologists from Europe and America proposed a new approach for classifying non-Hodgkin's lymphomas.[12] Rather than basing such classifications solely on the histopathologic characteristics of the tumor cells (ie, size, shape, and growth pattern), the authors proposed that immunologic characteristics, genetic characteristics, and the clinical characteristics of the disorders should all be taken into account in trying to identify homogeneous clinical pathologic entities.
The concepts in this Revised European-American Classification of Lymphoid Neoplasms (REAL) classification were tested in an international study of more than 1,400 cases from eight countries and four continents.[13] Five expert hematopathologists were able to diagnose lymphomas much more reproducibly than had been found in tests of previous systems, and the new clinical entities proposed in the REAL classification were distinctive. This approach was subsequently adopted as the World Health Organization (WHO) classification[14] and has become the standard approach for clinicians and investigators worldwide (Table 1).
Despite the advances embodied in the WHO classification, this is clearly not the last word. As has been true in the past, our knowledge of the biology of lymphomas continues to advance, and these new insights can lead to the recognition of clinically important subgroups of lymphomas that have not been previously known. The REAL and WHO classifications came into being in part because of earlier observations that led to descriptions of mucosa-associated lymphoid tissue (MALT) lymphoma, anaplastic large T/null cell lymphoma, and mantle cell lymphoma—subtypes that were not found in previous classifications.
Gene Array Studies
In recent years, the application of gene array technology has provided fascinating new insights into non-Hodgkin's lymphomas. Gene expression patterns have enabled the identification of two, and probably more, distinct subsets of diffuse large B-cell lymphoma.[15,16] Patients with a subtype termed germinal center type have twice the survival of another group with the activated B-cell subtype—at least when the same treatments are utilized (Figure 1). These different subtypes of diffuse large B-cell lymphoma cannot be distinguished morphologically.
Diffuse large B-cell lymphoma occurring in the mediastinum is clinically distinctive and associated with younger age and a female predominance that differs from diffuse large B-cell lymphoma involving other sites. Gene array studies have shown that this lymphoma is also distinctive in its gene expression pattern[17] and actually has a gene expression pattern more similar to Hodgkin's disease than to other diffuse large B-cell lymphomas.
Distinguishing between Burkitt's lymphoma and diffuse large B-cell lymphoma can sometimes be problematic. The strikingly different gene expression patterns seen in the two disorders allow this distinction to be made more accurately than can be done morphologically and can be used to guide therapy.[18] At least one study has found that the outcome of patients with follicular lymphoma might be better predicted by the gene expression pattern in the "normal" immune cells in the tumor than by the pattern in the tumor cells themselves.[19]
