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(American Journal of Pathology. 1999;155:2077-2086.)
© 1999 American Society for Investigative Pathology

Regular Articles

Primary Central Nervous System Lymphomas Are Derived from Germinal-Center B Cells and Show a Preferential Usage of the V4–34 Gene Segment

Manuel Montesinos-Rongen*, Ralf Küppers{dagger}, Dirk Schlüter{ddagger}, Tilmann Spieker§, Dirk Van Roost, Carlo Schaller, Guido Reifenberger*, Otmar D. Wiestler* and Martina Deckert-Schlüter*

From the Department of Neuropathology,*
University of Bonn Medical Center, Bonn; the Institute for Genetics and Department of Internal Medicine I,{dagger}
University of Cologne, Cologne; the Department of Medical Microbiology and Hygiene,{ddagger}
University of Heidelberg/Mannheim, Mannheim; the Institute for Pathology,§
University of Frankfurt, Frankfurt; and the Department of Neurosurgery,
University of Bonn Medical Center, Bonn, Germany

Primary central nervous system lymphomas (PCNSLs) have recently received considerable clinical attention due to their increasing incidence. To clarify the histogenetic origin of these intriguing neoplasms, PCNSLs from 10 HIV-negative patients were analyzed for immunoglobulin (Ig) gene rearrangements. All tumors exhibited clonal IgH gene rearrangements. Of the 10 cases, 5 used the V4–34 gene segment, and all of these lymphomas shared an amino acid exchange from glycine to aspartate due to a mutation in the first codon of the complementarity-determining region 1. No preferential usage of DH, JH, V{kappa}, J{kappa}, V{lambda}, or J{lambda} gene segments was observed. All potentially functional rearrangements exhibited somatic mutations. The pattern of somatic mutations indicated selection of the tumor cells (or their precursors) for expression of a functional antibody. Mean mutation frequencies of 13.2% and 8.3% were detected for the heavy and light chains, respectively, thereby exceeding other lymphoma entities. Cloning experiments of three tumors showed ongoing mutation in at least one case. These data suggest that PCNSLs are derived from highly mutated germinal-center B cells. The frequent usage of the V4–34 gene and the presence of a shared replacement mutation may indicate that the tumor precursors recognized a shared (super) antigen.




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