Background. There is general agreement that lymphocytic and histiocytic (L and H) cells, the variants of Reed-Sternberg cells in nodular lymphocyte- predominant Hodgkin's disease, belong to the B-cell lineage. However, the clonality of L and H cells remains controversial. Methods. We used complementarity-determining region 3 (CDR3) of the immunoglobulin heavy- chain gene as a clonal marker to study individual L and H cells isolated by micromanipulation from tissue sections of five patients with nodular lymphocyte-predominant Hodgkin's disease. The heavy-chain CDR3 of each cell was amplified by the polymerase chain reaction. The products were analyzed by gel electrophoresis, and representative amplification products from each patient were sequenced. Results. L and H cells whose heavy-chain CDR3 was related, indicating the presence of a clonal population, were detected in all five patients and were the dominant population in three. In four of the five patients, members of the clone were found in different nodules in the tissue section, different tissue blocks from the same tumor, or different lymph nodes from the same patient. The CDR3 sequences in each clone frequently contained nucleotide substitutions indicative of intraclonal mutation. Conclusions. Clonal populations of L and H cells occur in nodular lymphocyte- predominant Hodgkin's disease. Intraclonal variation in nucleotide sequences suggests that hypermutation of the heavy-chain CDR3 continues to occur among the clonal progeny.
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