Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells

Abstract

Among the four subtypes of Hodgkin disease (HD), lymphocyte-predominant (LP) HD is now generally considered as a separate entity. The B cell nature of the typical Hodgkin and Reed-Sternberg (HRS) cells and their variants (L and H, lymphocytic and histiocytic cells) in LP HD has long been suspected, but the question of whether these cells represent a true tumor clone is unclear. We previously demonstrated clonal Ig gene rearrangements in one case of LP HD. In the present study, five cases of LP HD were analyzed by micromanipulation of single HRS cells from frozen tissue sections and DNA amplification of rearranged Ig heavy chain genes from those cells. Clonal V gene rearrangements harboring somatic mutations were detected in each case. In three cases ongoing somatic mutation was evident. This shows that HRS cells in LP HD are a clonal tumor population derived from germinal center B cells. The pattern of somatic mutation indicates that HRS cells in LP HD are selected for antibody expression. This, and the presence of ongoing mutation discriminates LP from classical HD.

Figure 1

Genealogical trees explaining the relationship between clonally related sequences for LP HD patient 1 (a) and patient 2 (b). Each circle represents a different sequence. Numbers of single HRS cells with a specific sequence is given within the circles. Numbers and bases beside the arrows indicate the nucleotide position and type of exchange, respectively, defining a sequence. For intraclonal diversity within complementarity-determining region III (CDRIII), the most frequently occurring nucleotide was assumed to represent the unmutated variant.