V-H gene sequences from primary central nervous system lymphomas indicate derivation from highly mutated germinal center B cells with ongoing mutational activity

Primary central nervous system lymphoma (PCNSL) represents 1% to 3% intracr anial tumors. Most PCNSL are located in the brain, and 75% are large B-cell lymphomas. The largest subgroup of these tumors contains cells that resemb le centroblasts and has been labelled diffuse centroblastic (polymorphous) lymphoma. To investigate the cell of origin and the clonal history of these tumors, we have analyzed V-H gene of 5 cases of PCNSL, all confirmed by hi stological studies to be Epstein-Barr virus (EBV)-negative, high-grade diff use B-cell lymphomas. The V4-34 gene of the V(H)4 family was used in 4 of 5 cases. All V-H genes were found to have accumulated very high levels of so matic mutation (14% to 25%). In 3 of 5 cases, intraclonal nucleotide hetero geneity, including codon deletion in some clones in 1 case, was observed, i ndicating that the V-H genes were still under the influence of the somatic hypermutation mechanism. Analysis of the distribution of silent and replace ment mutations showed evidence for preservation of immunoglobulin structure in all cases.These results suggest that,a no evidence for germinal center formation in the brain tissue, PCNSL is derived from a B cell with features associated with location in a germinal center environment. (C) 1999 by The American Society of Hematology.