Clonality analysis and mutation status of IgVH genes in classic Richter's syndrome / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clonal rearrangements and mutation status of IgVH genes in classic Richter's syndrome, the relationship between molecular findings of IgVH gene and clinical outcome, and to deciper the possible molecular mechanism of transformation.</p><p><b>METHODS</b>The clonal rearrangements and mutation status of IgVH genes were analyzed in cases of classic Richter's syndrome by Genescan and sequencing. Immunohistochemical study for zeta-chain associated protein kinase 70 kDa (ZAP70), p53 and interferon regulation factor 4 (IRF-4) was also performed.</p><p><b>RESULTS</b>Samples of 18 cases of B-chronic lymphocytic leukemia (B-CLL)/ diffuse large B-cell lymphoma (DLBCL,78. 3%) had identical tumor cell clones, whereas DLBCL developed as a clonally independent neoplasm in 5 patients (21.7%). Among the clonally related group, 12 cases carried unmutated VH genes in both B-CLL and DLBCL components and VH3-23, VH3-74 and VH1-2 were accounted for the B-CLL transformation to DLBCL. Immunohistochemical study showed that the transformed DLBCL expressed CD5 in 32.1% of cases, CD23 in 14.3%, ZAP70 in 23.8%, p53 in 80.6% and IRF-4 in 82.6% of the cases respectively. Follow-up data were available in 17 patients with classic Richter's syndrome. The median survival period was 7 months. No significant difference in survival rate was obtained between the clonally related or unrelated groups, between IgVH gene mutated or unmutated groups, and between the groups with or without expression of ZAP70, p53 and IRF-4.</p><p><b>CONCLUSIONS</b>The ratio of clonally related transformed DLBCL from B-CLL to clonally unrelated DLBCL is 2:1. Clonal transformation to DLBCL predominantly occurs in B-CLL patients carrying unmutated IgVH genes. The biased IgVH gene usage suggests antigens are involved in classic Richter's syndrome. Molecular differences of IgVH genes and very poor clinical outcome of this group of transformed DLBCL indicate that there cases may be regarded as a distinct subset of DLBCL.</p>

Clonality analysis and mutational status of IgVH gene in Hodgkin variant of Richter syndrome / 中华病理学杂志

<p><b>OBJECTIVE</b>To detect the clonal relationship, the rearrangement, and the mutational status of IgVH gene; the influence of these molecular characteristics on the clinical outcome in Hodgkin variant of Richter syndrome; and the possible molecular pathogenesis in this transformation.</p><p><b>METHODS</b>The clonal rearrangements and mutational status of IgVH genes were analyzed in Hodgkin variant of Richter syndrome and B-CLL with Reed-Stemberg (R-S)-like cells by GeneScan analysis and sequencing. Semi-nest PCR based on laser capture microdissection was utilized to compare the clonal relationship between B-CLL and R-S/R-Slike cells. Immunohistochemical staining was used to detect the different expressions of ZAP70, p53, IRF-4 and LMP1 in the two components.</p><p><b>RESULTS</b>(1) 5/6 B-CLL cases transformed to Hodgkin lymphoma (HL)/R-S-like cells carried the mutated IgVH genes; (2) 2 cases of R-S cells and 1 case of R-S-like cells were clonally distinct from B-CLL clone and express LMP1, whereas 1 case of R-S-like cells was relating to the surrounding B-CLL cells and did not express LMP1; (3) 2/6 B-CLL cases transformed to HL convey VH4-34 and VH3-48 respectively.</p><p><b>CONCLUSIONS</b>(1) Richter transformation to HL/R-S-like cells evolves from the B-CLL which originates from the germinal center or post germinal center B cells, indicating that different lymphoma cells of different subtypes in Richter syndrome come from different B cell lineage and possibly involve a different pathogenesis and pathway; (2) HL and R-S-like cells evolve from either the B-CLL clone or may develop as a clonally unrelated lymphoma, the independent secondary malignancies are appear to be EBV-positive, possibly as a consequence of the underlying immunodeficiency; (3) The biased usage of IgVH genes suggested a role of antigens involved in the HL variant of Richter syndrome.</p>