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CHAPTER 96 HISTORICAL ASPECTS OF LYMPHOMA

CLASSIFICATION
PATHOLOGY OF LYMPHOMAS The classification of malignant lymphoma has been fraught with con-

troversy during much of the 20th century, with much needed consensus
Randy D. Gascoyne and Brian F. Skinnider reached during the past two decades. A detailed discussion of the his-
tory of lymphoma classification is beyond the scope of this chapter and
can be found elsewhere. 1
From Thomas Hodgkin’s description in 1832 of what became known
SUMMARY as Hodgkin’s disease to the first half of the 20th century, several types
2
of lymphomas with distinctive morphologic and clinical features were
The classification of malignant lymphomas has been a contentious issue dur- described using a variety of terms, including lymphoma, lymphosarcoma,
ing the past 50 years, undergoing numerous changes during its evolution. The reticulum cell sarcoma, and giant follicular lymphoma. However, many of
1
recent World Health Organization (WHO) classification of lymphoid neoplasms the terms were not used uniformly, resulting in significant misunderstand-
has gained worldwide acceptance by both pathologists and oncologists. It pro- ing, particularly between pathologists and clinicians. Starting in the 1930s,
vides a list of distinct diseases that are defined by a combination of morpho- several attempts were made to classify lymphomas and provide some uni-
logic, phenotypic, genetic, and clinical features, and attempts to correlate each formity of diagnosis, culminating in the Rappaport classification, initially
published in 1956, which divided lymphomas based on growth pattern,
disease with a cell of origin. Because the classification of lymphomas requires cell type, and stage of differentiation. Most importantly, this classification
3, 4
the integration of such diverse information, the diagnosis has become more demonstrated clinical relevance, showing that lymphomas with a nodular
complex compared to other solid malignancies. As a result, several ancillary pattern had a better prognosis than diffuse lymphomas.
studies have become useful in the diagnosis of lymphomas, which require In the 1960s and 1970s, an explosion of studies on the immune
special handling of biopsy material when a diagnosis of lymphoma is sus- system had a profound effect on our understanding of lymphocyte biol-
pected. The WHO classification identifies three major categories of lymphoid ogy and had a consequent effect on our understanding of malignant
malignancies: B-cell neoplasms, T and natural killer (NK) cell neoplasms, and lymphomas. Normal lymphocytes could now be classified into distinct
Hodgkin lymphoma. Two major categories are identified within the B-cell lineages (B, T, and natural killer [NK]), which could be determined by
and T/NK-cell neoplasms: precursor neoplasms and peripheral or mature expression of lineage-specific surface antigens and eventually by genetic
5,6
neoplasms. Unlike previous lymphoma classifications, the WHO classification analysis of B- and T-cell receptors. Several new lymphoma classifi-
does not group different lymphomas by clinical outcome or histologic grade. cation schemes were developed to incorporate the new immunologic
data, the most important being the Kiel classification (used primarily
7
It recognizes that each disease has distinctive clinical features and response to in Europe) and the Lukes and Collins classification (used primarily in
8
treatment and may have a spectrum of clinical aggressiveness that may cor- North America). By the 1970s, at least five classification schemes were
relate with histologic grade or gene expression patterns. The WHO classifica- widely used in different parts of the world. At the same time, clinical
tion recognizes that several of the diseases it describes are heterogenous and studies were beginning to show that some patients with aggressive lym-
likely include two or more distinct diseases that cannot be identified based phomas could be cured with combination chemotherapy. Oncologists
9
on current data, and remains open to incorporate new data as they become needed to interpret results of clinical trials performed in different insti-
available. One such source of new data for classifying lymphoma is the study tutions, a situation made difficult by the use of different classification
of gene expression profiling by complementary DNA microarray technology, schemes that were not easily translated among themselves.
which is providing new insights into the classification of diseases such as The problem was addressed by the United States National Cancer
diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Proteomic Institute, which convened a large group of investigators to determine
approaches will add further texture to the molecular taxonomy of lymphoma which classification scheme was best at predicting clinical outcome of
lymphoma. None of the classification schemes was identified as predict-
classification.
ing clinical outcome better than the other schemes. Therefore, patholo-
gists were advised to continue using one of the six classification schemes
studied, and a “Working Formulation” was developed so that oncologists
could translate clinical data derived in different institutions using different
classification schemes. Lymphomas were divided into 10 categories based
10
solely on morphologic features. To help clinicians deal with a large number
of lymphoma subtypes, the lymphomas were further grouped into three
clinical prognostic groups (clinical grades). Although the Working For-
mulation was not intended to be a standalone classification scheme, it was
used as such by many institutions, particularly in North America.
Acronyms and Abbreviations: ABC, activated B cell; ALCL, anaplastic large cell However, increasing phenotypic and genotypic data were further
lymphoma; ALK, anaplastic lymphoma kinase; DLBCL, diffuse large B-cell lymphoma; defining several distinctive lymphoma subtypes. The Working Formu-
EBV, Epstein-Barr virus; FISH, fluorescence in situ hybridization; GCB, germinal lation lumped different lymphomas into broad categories that were
center B cell; IGH, immunoglobulin heavy chain; LP, lymphocyte predominant; MALT, obscuring the distinctive features of the newly described entities. The
mucosa-associated lymphoid tissue; NF-κB, nuclear factor-κB; NK, natural killer; Working Formulation categories were based solely on morphologic fea-
PCR, polymerase chain reaction; PTCL, peripheral T-cell lymphoma; REAL, Revised tures and were not able to incorporate new immunologic and molecular
European-American Lymphoma; WHO, World Health Organization; ZAP-70, zeta- genetic data that were recognizing new types of lymphomas.
associated protein of 70 kDa. In the 1980s and 1990s, several new lymphoma entities were iden-
tified based on new immunologic and molecular genetic data. Although

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