The pathogenesis and clonal evolution of gastric
diffuse large B-cell lymphoma (DLBCL) and its relationship to extranodal
marginal zone B-cell lymphoma (MZBL), mucosa-associated lymphoid tissue (MALT) type, are still controversial. The aim of this study was to establish the clonality of morphologically distinct areas of gastric
lymphomas as well as their genetic relationship to each other. Six gastric
lymphomas, consisting of two MZBL, MALT type, two DLBCL, and two "
composite" lymphomas were subjected to
laser capture microdissection and subsequent PCR-based amplification of the
immunoglobulin heavy chain gene. One DLBCL showed a biclonal pattern of rearranged
immunoglobulin heavy chain (IgH) genes of two different areas without evidence of a common origin. Two composite DLBCL with areas of extranodal MZBL, MALT type, were also biclonal and displayed different IgH gene rearrangements in the small-cell and in the large-cell components, respectively. Sequencing of the CDR3 region revealed unique VH-N-D and D-N-JH junctions, thus corroborating the presence of two genuinely distinct
tumor clones in each of these three cases. In contrast, the remaining three gastric
lymphomas (one DLBCL and two MZBL, MALT type) showed IgH gene rearrangements in which CDR3 regions were identical in the different
tumor areas. Our results suggest that gastric DLBCL may be composed of more than one
tumor cell clone. Further, DLBCL may not necessarily evolve by transformation of a
low-grade lymphoma, but may also originate de novo. An ongoing emergence of new
tumor clones may considerably hamper molecular diagnosis and follow-up of gastric DLBCL.