Cabras A D, Candidus S, Fend F, Kremer M, Schulz S, Bordi C, Weirich G, Höfler H, Werner M
Departments of Pathology, Technische Universität München, München, Germany.
Lab Invest. 2001 Jul;81(7):961-7. doi: 10.1038/labinvest.3780308.
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.
胃弥漫性大B细胞淋巴瘤（DLBCL）的发病机制、克隆演变及其与结外边缘区B细胞淋巴瘤（MZBL）、黏膜相关淋巴组织（MALT）型的关系仍存在争议。本研究的目的是确定胃淋巴瘤形态学上不同区域的克隆性及其相互之间的遗传关系。对6例胃淋巴瘤进行了研究，其中包括2例MALT型MZBL、2例DLBCL和2例“复合型”淋巴瘤，采用激光捕获显微切割技术，随后基于聚合酶链反应（PCR）扩增免疫球蛋白重链基因。1例DLBCL在两个不同区域显示出重排免疫球蛋白重链（IgH）基因的双克隆模式，没有共同起源的证据。2例伴有结外MALT型MZBL区域的复合型DLBCL也是双克隆的，在小细胞和大细胞成分中分别显示出不同的IgH基因重排。互补决定区3（CDR3）区域的测序揭示了独特的VH-N-D和D-N-JH连接，从而证实了这3例中的每一例都存在两个真正不同的肿瘤克隆。相比之下，其余3例胃淋巴瘤（1例DLBCL和2例MALT型MZBL）显示出IgH基因重排，其中不同肿瘤区域的CDR3区域是相同的。我们的结果表明，胃DLBCL可能由不止一个肿瘤细胞克隆组成。此外，DLBCL不一定由低级淋巴瘤转化而来，也可能是原发起源。新肿瘤克隆的不断出现可能会严重阻碍胃DLBCL的分子诊断和随访。
