Biclonality of Gastric Lymphomas

Abstract

SUMMARY: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. (Lab Invest 2001, 81:961-967).T he two main groups of gastric lymphoma are extranodal marginal zone B-cell lymphoma (MZBL), mucosa-associated lymphoid tissue (MALT) type, and diffuse large B-cell lymphoma (DLBCL) . MZBL, MALT type, is composed of a monotonous, diffuse infiltrate of small lymphoid cells. DLBCL is characterized by a diffuse infiltrate of large malignant lymphoid blasts resembling centroblasts, plasmablasts, and immunoblasts. Occasionally, DLBCL shows both small-and large-cell components. These tumors have been called "composite" lymphomas, their histologic spectrum ranging from cases with well separated small-and large-cell components, to tumors in which these components are intermingled (De Jong et al, 1997;De Wolf-Peeters and Achten, 1999).The histogenesis of gastric DLBC lymphoma, as well as its possible clonal relationship to concomitant or preceding low-grade components, has been strongly debated recently and is still not fully clarified. The clonality of B-cell non-Hodgkin's lymphomas can be assessed by the PCR analysis of rearranged immunoglobulin heavy chain (IgH) genes that vary in size in different neoplastic cell populations (Trainor et al, 1991). Several studies comparing the patterns of clonal IgH gene rearrangement between large-cell and small-cell areas in the same gastric B-cell lymphoma have demonstrated a common clonal origin of both components (Chan et al...

Oligoclonality of a "composite" gastric diffuse large B-cell lymphoma with areas of marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type

“…The analysis of the small-cell component of the antrum revealed a third malignant clone as a new finding. Indeed, a gastric lymphoma with three different neoplastic clones has never been reported, to the best of our knowledge, and reports of only five biclonal gastric lymphomas have been published so far [1,16,27].…”

“…* D region gene in reverse orientation. For sequence analysis of the antrum see also Cabras et al [1] IgH have indicated that the neoplastic B-cells originate in a post-germinal center cell [22]. Moreover, the detection of "ongoing mutations" has suggested an important role for antigenic stimulation in the clonal expansion of these tumor cells [7].…”

“…Thus, not only were the MZBL of MALT type components of the corpus and of the antrum clonally independent, but even within the same anatomical site each morphologically distinct tumor component (small-and large-cell) appeared to be composed of different coexisting neoplastic clones. In our first analysis [1], where only the small-and the large-cell components of the antrum were analyzed, we classified this "composite" lymphoma as biclonal. The analysis of the small-cell component of the antrum revealed a third malignant clone as a new finding.…”

“…In a recently published study, we showed that the "composite" tumor in the antrum had a biclonal IgH gene rearrangement in the small-and large-cell components [1]. We have now analyzed the second "composite" tumour in the corpus which also consisted in well-separated areas of DLBCL.…”

Molecular and cytogenetic characterization of expanded B-cell clones from multiclonal versus monoclonal B-cell chronic lymphoproliferative disorders

“…This might even be true when the coexisting clones display clearly distinct immunophenotypic and cytogenetic, as well as clinical, features. [20][21][22] In order to test this hypothesis, in the present study we compared the B-cell receptor (BCR) repertoire and molecular profile, as well as the phenotypic, cytogenetic and hematologic features of CLL-like and non-CLL-like clones (n=228) from multiclonal (n=41 cases) versus monoclonal cases [n=143, including both CLL and CLL-like MBL (n=128), as well as cases of B-CLPD other than CLL and non-CLL-like MBL (n=15)]. …”