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1208 Part VII Hematologic Malignancies

HRS cell

Naive GC Common
B cell B cell lymphoma Separate additional
precursor
transforming events?

First
transforming
event(s)?
B-NHL
cell
Germinal
center

Fig. 74.2 SCENARIO FOR THE GENERATION OF COMPOSITE LYMPHOMAS. Composite lympho-
mas are very rare combinations of two distinct lymphomas, often a classical HL and an NHL. Detailed
molecular analysis of rearranged Ig V genes in several combined HL and B-cell derived NHL revealed that,
in most instances, the two lymphomas are clonally related. Notably, the pattern of both shared and distinct
V gene mutations in the majority of these cases revealed that the two lymphomas share a common precursor,
but developed separately from this precursor. The direct clonal relationship of HRS cells with typical GC B
cell–derived NHL is a further strong argument for a GC derivation of HRS cells. The horizontal line within
the cells indicates an Ig V region gene; the vertical lines indicate somatic Ig V gene mutations. (Modified from
Bräuninger A, Hansmann ML, Strickler JG, et al: Identification of common germinal center B-cell precursors in two
patients with both Hodgkin’s disease and non-Hodgkin’s lymphoma. New Engl J Med 340:1239, 1999.)

The issue of potential subpopulations among the HRS cell clone occur either before or after an NHL in the same patient. There are a
with specific features in terms of proliferative potential and chemo- few cases where the two lymphomas are not related to each other and
therapy resistance was also addressed by searching for side population hence represent the chance occurrence of two unrelated malignancies
cells, which are defined as cells that extrude the Hoechst dye 33342, developing in parallel in a patient. However, in most composite and
usually because they express drug transporters of the ABC family, sequential HL and NHL that have been molecularly studied for their
such as the multidrug resistance 1 gene. In several types of tumors, clonal relationship, it was found that the lymphomas share a common
side population cells were shown to share features with cancer stem origin, even in instances where sequential lymphomas occurred several
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cells (e.g., increased proliferative potential and chemotherapy resis- years apart from each other. The detailed study of the rearranged
tance). Side population cells were indeed detected at low frequency Ig V genes of such cases revealed that although, in many cases, the
(about 0.5% of cells) in some HL cell lines, and these cells showed clonally related V region genes of the lymphomas share a number
increased resistance to chemotherapeutic drugs. 15,16 The side popula- of somatic mutations, there are often additional mutations that were
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tion cells had the phenotype of small Hodgkin cells and they were present only in the HRS cells and others only in the NHL B cells.
positive for CD30 and negative for CD19 and CD20. Hence these This showed that the two lymphomas have a common precursor,
cells are different from the cells identified earlier as potential HRS most likely a mutating GC B cell, and that the two lymphomas most
stem cells. Notably, side population cells were able to reestablish the likely developed from two distinct members of the GC B cell clone
full HRS cell clone upon subcloning. However, not all HL cell lines (Fig. 74.2). Thus these composite lymphomas usually do not represent
showed side population cells, 15,16 arguing against a general role of the transformation of one lymphoma into the other but, rather, the
these cells in the maintenance of the HRS cell clone. Moreover, parallel development of the two malignant clones from a common,
although side population cells were also identified in cell suspensions premalignant precursor cell. It is likely that some transforming events
of HL lymph nodes, it remains to be clarified whether these cells were already present in the common precursor, but distinct daughter
belong to the HRS cell clone. Thus, there are exciting developments cells of this GC B cell later acquired different mutations, leading to
regarding the potential existence of subpopulations among the HRS the generation of the two distinct B-cell malignancies (Fig. 74.2).
cell clones with specific biologic features, but additional studies are Therefore composite lymphomas are intriguing models to study the
needed to characterize these cells and reveal their relevance for the multistep transformation process in lymphomagenesis. In initial studies
HRS clone in vivo. of several composite lymphomas for shared and distinct transforming
events, examples for such genetic lesions were indeed identified.
A further important aspect of the molecular studies of composite
Lessons From Composite Lymphomas lymphomas is that they provide further evidence for the derivation
of HRS cells in classical HL from GC B cells, because the clonal
Composite lymphomas are very rare lymphomas in which two distinct relationship with shared and distinct somatic Ig V gene mutations
lymphomas, often an HL and a non-Hodgkin lymphoma (NHL), of an HRS cell clone and a typical GC B cell–derived lymphoma
occur in the same patient. In a strict definition of composite lymphoma, (e.g., follicular lymphoma or diffuse large B-cell lymphoma) strongly
this happens concurrently, but there are also cases where an HL may supports a common GC B-cell origin of both malignancies.