ORIGIN OF NODULAR LYMPHOCYTE-PREDOMINANT HODGKINS-DISEASE FROM A CLONAL EXPANSION OF HIGHLY MUTATED GERMINAL-CENTER B-CELLS

Background The atypical cells of nodular lymphocyte-predominant Hodgki n's disease, designated lymphocytic and histiocytic (L&H) cells, have a B-cell phenotype. To clarify the clonality of these cells, we studie d rearranged immunoglobulin genes for the variable region of the heavy chain (V-H genes) in individual L&H cells from 11 patients with nodul ar lymphocyte-predominant Hodgkin's disease. We also studied the expre ssion of immunoglobulin light chains by those cells in six of the same patients. Methods Single CD20+ L&H cells were isolated from frozen se ctions by a technique of micromanipulation. The rearranged V-H genes o f these cells were amplified by the polymerase chain reaction (PCR), s equenced, and compared with germ-line V-H genes. Immunoglobulin light- chain messenger RNA (mRNA) was detected by in situ hybridization. Resu lts Of 615 L&H cells isolated from all the frozen sections, 160 yielde d PCR products. In each of the 11 patients, the L&H cells that could b e evaluated had identically rearranged V-H genes, whether they were is olated from the same nodule, different nodules, or different blocks of tissue. All the V-H sequences derived from the L&H cells were highly mutated (7.5 to 27.2 percent). in two cases the coding capacity of the V-H genes was completely or partially disrupted by mutations. Intracl onal diversity was found in six cases, and monotypic immunoglobulin li ght-chain mRNA was found in six. Conclusions The L&H cells of nodular lymphocyte-predominant Hodgkin's disease represent a monoclonal expans ion of B cells. The high load of V-H gene mutations and signs of intra clonal diversity suggest a relation between L&H cells and germinal-cen ter B cells at the centroblastic stage of differentiation. (C) 1997, M assachusetts Medical Society.