Abstract
Classical Hodgkin's disease (HD) and B-cell non-Hodgkin lymphoma (NHL) occasionally occur in the same patient. Such composite lymphomas represent interesting models to study the pathogenesis of B-cell lymphomas and the relationship between HD and B-cell NHL. We analyzed two composite lymphomas (a combination of classical HD with follicular lymphoma [FL] and a combination of classical HD with B-cell chronic lymphocytic leukemia [B-CLL]) by micromanipulation of single cells from tissue sections and amplification of immunoglobulin V region genes for the clonal relationship of the tumor cells. In both cases, clonally related variable (V) genes with both shared as well as distinct somatic mutations were obtained from the two lymphomas, showing that in each of the cases the distinct tumor cells were members of a common germinal center (GC) B-cell clone. FL cells from two different lymph nodes of patient 1 showed a similar mutation pattern, suggesting that infiltration of these lymph nodes by tumor cells was not restricted to a particular FL cell or subclone. In the FL, a single cell was identified with a mutation signature indicating that premalignant cells can persist in the tissue. The cases presented here further underline the close relationship between HD and B-cell NHL and the role of the GC in lymphomagenesis. Whereas the latter was already suggested for FL and HD, the present study indicates that also in the B-CLL subset characterized by mutated Ig genes, important steps in malignant transformation happen in the GC, and that HRS cells can derive from CD5-positive B cells.
Highlights
Because immunoglobulin (Ig) variable (V) region genes are highly diverse and specific for B cells, they represent ideal molecular markers for B-lineage cells and the clonal composition of B-cell populations
In the two composite lymphomas analyzed in the present study, the molecular Ig gene analysis revealed that in each case, the Hodgkin and Reed-Sternberg (HRS) and B-non-Hodgkin lymphoma (NHL) cells were clonally related
The presence of shared as well as distinct somatic mutations in the rearranged Ig genes indicates that in both cases the common precursor was a germinal center (GC) B cell (Fig. 2C). This situation is reminiscent of three other combinations of classical Hodgkin’s disease (HD) and B-cell NHL previously described, because in these cases the lymphomas derived from common precursors, and the lymphomas harboured shared as well as distinct V gene mutations [10,11]
Summary
Because immunoglobulin (Ig) variable (V) region genes are highly diverse and specific for B cells, they represent ideal molecular markers for B-lineage cells and the clonal composition of B-cell populations. HD and a B-cell non-Hodgkin lymphoma (NHL) occur in the same patient, either simultaneously or sequentially [8] Such lymphomas represent interesting models to study the pathogenesis of B-cell lymphomas and the relationship between HD and B-cell NHL. Classical Hodgkin’s disease (HD) and B-cell non-Hodgkin lymphoma (NHL) occasionally occur in the same patient Such composite lymphomas represent interesting models to study the pathogenesis of B-cell lymphomas and the relationship between HD and B-cell NHL. Conclusions: The cases presented here further underline the close relationship between HD and B-cell NHL and the role of the GC in lymphomagenesis Whereas the latter was already suggested for FL and HD, the present study indicates that in the B-CLL subset characterized by mutated Ig genes, important steps in malignant transformation happen in the GC, and that HRS cells can derive from CD5-positive B cells
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