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U-M CCC - Michigan Oncology Journal Fall 2000

The Revised European-American Classification of Lymphoid Neoplasms (REAL classification)

Charles W. Ross, M.D.
Associate Professor of Pathology,
Section of Hematopathology
Director, Clinical Flow Cytometry Laboratory

"Another lymphoma classification?! Get REAL!" Such was the expression of skepticism and apprehension from many quarters at the announcement of a new classification for lymphoid neoplasia, published in 1994 as the REAL classification (1). Yet, most would agree that some revision or refinement of the previous classifications was long overdue. The Working Formulation (2), published in 1982, was based solely on histopathologic criteria. There was a clear need to update that classification by incorporating the wealth of immunophenotypic, molecular genetic, and clinical information that had accrued since 1982. Similar shortcomings were apparent in the Kiel classification (3), the European counterpart of the Working Formulation. Based primarily on morphology, the Kiel classification also suffers from problems of poor reproducibility among hematopathologists. Furthermore, it does not include primary extranodal lymphomas, except for mycosis fungoides.

The REAL classification developed during meetings between 19 prominent European and American hematopathologists (the self-ordained "International Lymphoma Study Group" or ILSG). They worked to establish consensus about the categories of lymphoid neoplasia, based not just on morphology but with immunologic, molecular genetic and clinical correlates when possible. The papers published by the ILSG (1,4) summarize the defining features of the consensus disease entities, along with some information about clinical presentations and postulated normal counterparts in the immune system.

The REAL classification is comprehensive, including Hodgkin's and non-Hodgkin's lymphomas, as well as the lymphoid leukemias. Three major categories of lymphoid neoplasia were agreed upon: B-cell, T/natural killer (NK)-cell, and Hodgkin's disease. Table 1 lists the B-cell and T/NK-cell entities in the REAL classification, along with corresponding terminology from the Working Formulation for comparison. Within each of the major disease categories, the consensus panel recognized "definite," "provisional," and "unclassifiable" (not further classifiable) subsets. The classification is intended to be a flexible framework, subject to modification as new information and better understanding of the pathobiology ensues.

B-cell Neoplasms

The REAL classification incorporated several distinctive types of B-cell lymphoma that had not yet been described when the Working Formulation was introduced. These definite entities include: mantle cell lymphoma; primary mediastinal large B-cell lymphoma; and extranodal marginal zone B-cell lymphoma. The latter entity also goes by the somewhat cumbersome name of "low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)-type."

The ILSG also gave provisional recognition to nodal marginal zone B-cell lymphoma and splenic marginal zone B-cell lymphoma. These categories were not previously recognized as unique disease entities in the Working Formulation. Although they have been described in some detail in the recent literature, they are uncommon disorders. The ILSG had insufficient collective experience with them to be confident they were distinct diseases, hence the provisional listing.

Finally, the REAL classification has dropped the Working Formulation distinction between diffuse large B-cell lymphoma and large cell immunoblastic lymphoma. This was a distinction that suffered from very poor reproducibility among hematopathologists; some debate still smolders about its clinical significance.

T-cell and NK-cell neoplasms

In general, this category is diagnostically more challenging than B-cell neoplasms. These are relatively uncommon disorders (particularly in the United States and Europe), and there is no good clonal marker short of gene rearrangement or cytogenetic studies. In mature T-cell neoplasia, cytologic features and cytologic grade have not been that useful in defining disease entities or predicting clinical outcome, unlike the situation for many B-cell neoplasms. Instead, specific body sites of presentation and clinical features seem to be very important in defining these entities. Hence, the REAL classification recognizes several unusual subtypes of peripheral T-cell neoplasia, including subcutaneous panniculitic T-cell lymphoma; hepatosplenic g d T-cell lymphoma; intestinal (enteropathy-type) T-cell lymphoma; anaplastic large cell lymphoma (T-and null-cell types); and adult T-cell lymphoma/leukemia (associated with HTLV-1).

Hodgkin's Disease

Although there have been great advances in understanding the pathobiology of Hodgkin's disease, nomenclature has changed little since the Rye classification was published in 1966 (5). The REAL classification added lymphocyte-rich classical Hodgkin's disease as a provisional entity.

What's Next?

In the six years since its inception, the REAL classification has gained a large measure of acceptance. Deficiencies have been recognized, but this is normal. The framers intended it be a flexible document, subject to modifications to fit the times. The following are several examples of shortcomings in the initial version of REAL:

• It fails to set clinically relevant and reproducible criteria for the grading of follicular lymphomas. The lack of reproducibility in the grading of these common neoplasms has been a source of embarrassment for hematopathologists (many of whom are shy and retiring creatures). Another source of confusion about the follicular lymphomas concerns reporting of any associated diffuse areas. Is quantification of diffuse areas clinically relevant? There is no consensus.
• It provides little or no guidance in the grading of MALT-type lymphomas. This is an area needing more research.
• REAL does not seriously address the complex area of primary cutaneous lymphomas (other than mycosis fungoides). The European Organization for Research and Treatment of Cancer (EORTC) has recently published a brave essay bringing some order to this complex subject (6), but much work remains to be done.
• The provisional category of "high-grade B-cell lymphoma, Burkitt-like" suffers from very poor reproducibility among hematopathologists.
• The classification does not include several recently described entities, such as primary effusion lymphoma (associated with human herpesvirus-8) or extranodal NK/T-cell lymphoma of nasal type.
• There is no well-defined gold standard for the diagnosis of anaplastic large cell lymphoma (ALCL), a disease that may have a rather broad morphologic spectrum. Primary cutaneous ALCL seems to be different biologically from the systemic form, and the cutaneous form may pose difficulties in differential diagnosis with lymphomatoid papulosis or mycosis fungoides.

Ongoing discussions and debates among pathologists and clinicians have helped to bring these and other problems into focus. Concerns about diagnostic reproducibility and clinical relevance are driving changes in the classification. As a result, an updated and revised REAL is being incorporated into the upcoming World Health Organization (WHO) Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues (7). The WHO classification is being formulated by ten committees of pathologists under the auspices of the European Association of Hematopathologists and the Society for Hematopathology, in conjunction with an advisory committee of international hematologists and oncologists. It is intended to be a comprehensive classification of hematologic malignancies, including lymphoid, myeloid, histiocytic and mast cell types. "Another classification? Says WHO!"

References

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