HISTORICAL PERSPECTIVE

Table 1 Rappaport Classification

Nodular Diffuse

Lymphocytic, well differentiated

Lymphocytic, poorly differentiated

Mixed cell (lymphocytic and histiocytic)

Histiocytic

Undifferentiated

were included together in the category of diffuse histiocytic tumors. This was later recognized to be a problem, as virtually all of these neoplasms proved to be of lymphoid lineage and had no developmental relationship to tumors of histiocytes or so-called tissue-based macrophages. Therefore, the late 1960s saw the Rappaport classification fall into disfavor as it was replaced by a number of other classifications based upon new knowledge of the immune system. The two best known were the Lukes and Collins and the Kiel classifications. The former scheme was used heavily in North America, while the latter derives from Kiel, Germany and is still used frequently today in some parts of Europe. These two ‘‘competing’’ classifications incorporated new immunological data together with morphological assessment as the primary basis of classification. For the first time, lymphomas were separated into B- and T-cell types and clearly recognized in the context of normal lymphoid cell ontogeny. However, these two schemes were part of an explosion of different classification proposals that flooded the literature in the 1970s and led to mass confusion. No well-defined nomenclature existed to translate from one classification to another, rendering many clinicopathologic analyses virtually uninterruptible.

Our clinical colleagues recognized the problems with the various pathological classifications in use throughout the world, and sought to bring some order to the chaos. Thus, in the late 1970s and early 1980s, a large multicenter study was organized to develop a working nomenclature for translating from one classification to another. This effort brought together almost 1200 cases from North America and Europe

as well as most of the recognized lymphoma classification experts in the world. The result was the Working Formulation for Clinical Usage (Working Formulation, WF).

As this effort was largely clinically driven, the resultant scheme separated the lymphoid tumors based primarily on their survival characteristics. Although never intended as a specific classification scheme, the WF became the predominant tool used throughout the world for the classification of malignant non-Hodgkin’s lymphomas. The details of the WF are provided in Table 2. As is evident from the proposal, the diseases are separated into clinical grades and the scheme clearly lumps together lymphomas of various types and lineages. No effort was made to separate B-cell from T-cell diseases, and the effectiveness of therapy during the era in which these cases were accrued left some wondering whether this was really an analysis of the natural history of many of the proposed disorders. Nonetheless, this scheme remained

Table 2 Working Formulation for Clinical Usage

Low grade

Small lymphocytic lymphoma (chronic lymphocytic leukemia) plasmacytoid differentiation

Follicular lymphoma, small cleaved

Follicular lymphoma, mixed small and large cell Intermediate grade

Follicular lymphoma, large cell type Diffuse small-cleaved cell lymphoma

Diffuse mixed, small and large cell lymphoma

Diffuse large cell lymphoma, cleaved and noncleaved types High grade

Diffuse large cell lymphoma, immunoblastic type Lymphoblastic lymphoma

Small noncleaved lymphoma, Burkitt’s Miscellaneous

Composite Mycosis fungoides True histiocytic

Extramedullary plasmacytoma Unclassifiable

Other

popular throughout the world until the hematopathologists got themselves properly organized and developed the REAL classification (Revised European–American Classification of Lymphoid Neoplasms) in 1994. The REAL classification was put forward by the International Lymphoma Study Group (ILSG), a small group comprised of North American and European hematopathologists. The REAL classification was essentially a consensus list of lymphoid neoplasms that pathologists could recognize using currently available techniques and that appear to be distinct disease entities. The most recent classification scheme for non-Hodgkin’s lymphomas was put together by the World Health Organization classification (WHO). The various committees of the WHO proposal were for the most part under the leadership of different ILSG members; thus, the WHO classification as shown in Table 3 is essentially a recapitulation of the REAL scheme with minor modifications.

The approach to classification of non-Hodgkin’s lymphomas uses all available information including morphology, immunophenotype, genetic and cytogenetic data, and clinical features to define a disease entity. Monoclonal antibody technology and refinements in molecular genetic techniques have been paramount to our ability to recognize these entities and specifically define diseases using routinely archived paraffin material. Several caveats are important to understand the new approach to classification. Firstly, the relative importance of any of these features varies among disease entities, and there is no one ‘‘gold standard.’’ Some diseases continue to be defined primarily by morphology, with immunophenotype only required in difficult cases. Other disorders have a unique or ‘‘signature’’ immunophenotype, such that one would hesitate to make the diagnosis in the absence of the immunophenotype. Still other lymphoma subtypes have a specific molecular genetic alteration that essentially defines the disease. As our level of understanding has improved, we are now recognizing that many of these diseases have unique genetic alterations that translate into the production of highly specific proteins. These then serve as unique immunophenotypic markers of disease and have greatly facilitated the routine application

Table 3 World Health Organization Classification

B-cell neoplasms

Precursor B-cell neoplasms

Precursor B-cell lymphoblastic leukemia=lymphoma

Mature B-cell neoplasms

Small lymphocytic lymphoma=chronic lymphocytic leukemia B-cell prolymphocytic leukemia

Lymphoplasmacytic lymphoma Splenic marginal zone lymphoma Hairy cell leukemia

Plasma cell myeloma

Monoclonal gammopathy of undetermined significance Solitary plasmacytoma of bone

Extraosseus plasmacytoma Primary amyloidosis Heavy chain disease

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)

Nodal marginal zone lymphoma Follicular lymphoma

Mantle cell lymphoma Diffuse large cell lymphoma

Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma

Burkitt’s lymphoma=leukemia

T-cell neoplasms (including natural killer (NK) cell neoplasms)

Precursor T-cell neoplasms

Precursor T-cell lymphoblastic lymphoma=leukemia

Mature T-cell neoplasms

T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia Aggressive NK cell leukemia

Adult T-cell leukemia=lymphoma (HTLV 1) Mycosis fungoides

Se´zary syndrome

Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis

Extranodal T=NK cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma Angioimmunoblastic T-cell lymphoma

(Continued)