Lymphoma Classification Proposal: Clarification

In a recent issue of Blood, the International Lymphoma Study Group (ILSG) presented a list of lymphoid neoplasms derived by consensus, and suggested that it could serve as a practical classification of these tumors for both pathologists and clinicians.’ Each of the entities on the list represents a clearly recognizable and distinct disease, based on currently available morphologic, immunologic, and genetic techniques, with a characteristic clinical behavior. Dr Saul Rosenberg, in an accompanying editorial, indicated his concern that this list of neoplasms should not yet be used in clinical practice? We believe that the implementation of a broadly based international consensus on lymphoma classification is long overdue, and that further delay is not warranted. We fear that these concerns may lead to unnecessary hesitation on the part of pathologists and clinicians to recognize these clinicopathologic entities. Therefore, we would like to address these concerns and offer the following clarifications of our proposal. First, there is concern about the extent to which this list of neoplasms will be accepted by other hematopathologists. The history of lymphoma classification would appear to give credence to this concern, because previous generations of pathologists have been unable to agree on a classification system; even the working formulation did not represent a consensus because it was rejected by 2 of the 12 pathologists involved, Drs Karl Lennert and Robert Lukes, at the time of its publication. However, we believe that most of the entities in our classification are already being diagnosed by most hematopathologists; our list is just a description of what is already being done. The main reason that a consensus among pathologists on lymphoma classification is now possible is the availability of objective immunophenotyping and genetic data to resolve areas that were controversial when morphology was the only criterion for defining entities. As we stated in our paper, we recognize that our list will require updating and modification, and we look forward to working with other hematopathologists to broaden and build upon this consensus. A second concern that has been raised is the availability of immunophenotyping and genetic studies, which are an important component of the definition of these neoplasms, in parts of the United States. Our experience as consultants suggests that this concern is not warranted; we find that most practicing pathologists are well aware of the need for special studies on a variety of specimen types, including immunophenotyping of lymphoid and other neoplasms, hormone receptor assays, etc, and are capable of either performing these tests themselves or preserving tissue so that others can perform such studies when needed. Furthermore, a large panel of antibodies for immunophenotyping on paraffin sections is now available and will permit most tumors to be adequately characterized on routinely processed, formalin-fixed, paraffin-embedded biopsy specimens. Finally, immunophenotyping studies are not required to make every diagnosis in every case. As a general principle, morphologic, clinical and immunologic/genetic features are all taken into account in establishing a diagnosis. However, many individual cases of lymphoma can be diagnosed on morphologic grounds alone, providing that histologic sections of reasonable quality are available. In any morphologically or clinically atypical case, immunophenotyping and/or genetic studies may be helpful in establishing a diagnosis. These studies markedly improve diagnostic accuracy and reproducibility among pathologi~ts.~ It would indeed be a major step backwards to suggest that the immunophenotype should not be part of the definition of a lymphoid neoplasm. We do not think that pathologists should ignore all the advances in immunology and genetics of the last 20 years and continue to classify lymphomas according to the techniques of the 1960s. It strikes us as curiously paradoxical that classification according to a putative cell of origin is intrinsic to virtually all schemes of tumor classification in other organ systems, and yet it is questioned in the United States for lymphomas-the one area in which we actually have objective evidence for the normal counterpart of most of the malignancies. Another concern is that our classification is not adequately supported by a clinical database. A pathologic classification of neoplasms is, by definition, a listing of distinct disease entities, based on features that can be recognized by pathologists: chiefly morphology, buttressed to a variable extent by special techniques. For pathologists to make the diagnoses, the entities must be defined by these features. Clinical studies to define their clinical spectrum and optimal treatment are essential, but these are not typically the responsibility of the pathologist, and cannot be conducted until pathologists can recognize the entities. It is important to remember that in the working formulation study there was no consensus on the pathologic classification, so that the investigators were working in reverse: defining pathologic entities by clinical prognostic data. This is not the case with our proposal. We did not define any new entities: all of the diseases in our classification have been described in the literature, and for most of them there are numerous studies to show that they have distinctive clinical features. We question the need for more data to show that precursor Band T-cell neoplasms, B-cell chronic lymphocytic leukemia (B-CLL), Waldenstrom’s macroglobulinemia, follicular lymphoma, hairy cell leukemia, plasma cell myeloma, diffuse large B-cell lymphoma, Burkitt’s lymphoma, mycosis fungoides, and adult T-cell lymphoma/leukemia (ATLL) are distinct entities. Even for the more recently described or uncommon entities such as mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic lymphoma, and angiocentric lymphoma, there is already