title: IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution.
abstract: Approximately 5% of B-cell chronic lymphocytic leukemia (B-CLL) patients develop a secondary aggressive lymphoma, usually of diffuse large B-cell type (DLBCL), termed Richter's transformation (RT). Rarely, classic Hodgkin lymphoma (HL) is observed. Published small series suggest that tumor cells in DLBCL and HL can be clonally identical to the B-CLL clone or arise as an independent, secondary lymphoma. We describe the morphology, immunophenotype, and clinical features of 34 classic RT patients with DLBCL, 6 cases of B-CLL with HL, and 8 cases with scattered CD30-positive Hodgkin and Reed-Sternberg (HRS)-like cells. The clonal relationship of the 2 components was analyzed using sequencing analysis of immunoglobulin heavy chain variable region (IgVH) genes. In classic RT, 18/23 B-CLL cases (78%) showed clonal progression to DLBCL with identical IgVH sequences in both lymphoma components, whereas in 5 cases (22%) the DLBCL was clonally unrelated. Among clonally related RT samples, 73% carried unmutated IgVH genes, whereas 4/5 unrelated cases were mutated. Immunophenotypically, most cases of DLBCL irrespective of clonal relatedness showed significant differences in phenotype compared with the B-CLL, with common loss of CD5 and CD23. Using immuno-laser capture microdissection, sequencing of the IgVH CDR3 region of isolated HRS cells showed that 2/2 cases with HL were clonally unrelated, whereas they were clonally identical in 1/2 cases of B-CLL with scattered HRS-like cells. HRS or HRS-like cells in all 3 unrelated cases showed evidence of Epstein-Barr virus infection. Of interest, 5/6 cases of B-CLL with HL, and 5/6 cases of B-CLL with HRS cells showed mutated IgVH genes.
authors: Institute of Pathology, University of Würzburg, Germany.
authors: Zhengrong
authors: Z
authors: Mao
authors: Leticia
authors: L
authors: Quintanilla-Martinez
authors: Mark
authors: M
authors: Raffeld
authors: Manfred
authors: M
authors: Richter
authors: Jens
authors: J
authors: Krugmann
authors: Christof
authors: C
authors: Burek
authors: Elena
authors: E
authors: Hartmann
authors: Thomas
authors: T
authors: Rudiger
authors: Elaine S
authors: ES
authors: Jaffe
authors: Hans Konrad
authors: HK
authors: Müller-Hermelink
authors: German
authors: G
authors: Ott
authors: Falko
authors: F
authors: Fend
authors: Andreas
authors: A
authors: Rosenwald
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte; D006689:Hodgkin Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007834:Lasers; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region