Common germinal-center B-cell origin of the malignant cells in two composite lymphomas, involving classical Hodgkin's disease and either follicular lymphoma or B-CLL

Background: Classical Hodgkin's disease (HD) and B-cell non-Hodgkin lymphom a (NHL) occasionally occur in the same patient. Such composite lymphomas re present interesting models to study the pathogenesis of B-cell lymphomas an d the relationship between HD and B-cell NHL. Materials and Methods: We analyzed two composite lymphomas (a combination o f 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. Results: In both cases, clonally related variable (V) genes with both share d as well as distinct somatic mutations were obtained from the two lymphoma s, 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 I showed a similar mutation pattern, suggesting that infiltration of these lymph nodes by tumor cells was not restricted to a p articular 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. Conclusions: The cases presented here further underline the close relations hip between HD and B-cell NHL and the role of the GC in lymphomagenesis. Wh ereas the latter was already suggested for FL and HD, the present study ind icates that also in the B-CLL subset characterized by mutated Ig genes, imp ortant steps in malignant transformation happen in the GC, and that HRS cel ls can derive from CDS-positive B cells.